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Current state of stem cell-based therapies: an overview

Riham mohamed aly.

1 Department of Basic Dental Science, National Research Centre, Cairo, Egypt;

2 Stem Cell Laboratory, Center of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt

Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative strategies may one day become a treatment for a wide range of vexing diseases. In fact, the past few years witnessed, a rather exponential advancement in clinical trials revolving around stem cell-based therapies. Some of these trials resulted in remarkable impact on various diseases. In this review, the advances and challenges for the development of stem-cell-based therapies are described, with focus on the use of stem cells in dentistry in addition to the advances reached in regenerative treatment modalities in several diseases. The limitations of these treatments and ongoing challenges in the field are also discussed while shedding light on the ethical and regulatory challenges in translating autologous stem cell-based interventions, into safe and effective therapies.

Introduction

Cell-based therapy as a modality of regenerative medicine is considered one of the most promising disciplines in the fields of modern science & medicine. Such an advanced technology offers endless possibilities for transformative and potentially curative treatments for some of humanities most life threatening diseases. Regenerative medicine is rapidly becoming the next big thing in health care with the particular aim of repairing and possibly replacing diseased cells, tissues or organs and eventually retrieving normal function. Fortunately, the prospect of regenerative medicine as an alternative to conventional drug-based therapies is becoming a tangible reality by the day owing to the vigorous commitment of the research communities in studying the potential applications across a wide range of diseases like neurodegenerative diseases and diabetes, among many others ( 1 ).

Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative strategies may one day become a treatment for a wide range of vexing diseases ( 2 ). In fact, the past few years witnessed, a rather exponential advancement in clinical trials revolving around stem cell-based therapies. Some of these trials resulted in remarkable impact on various diseases ( 3 ). For example, a case of Epidermolysis Bullosa manifested signs of skin recovery after treatment with keratinocyte cultures of epidermal stem cells ( 4 ). Also, a major improvement in eyesight of patients suffering from macular degeneration was reported after transplantation of patient-derived induced pluripotent stem cells (iPSCs) that were induced to differentiate into pigment epithelial cells of the retina ( 5 ).

However, in spite of the increased amount of publications reporting successful cases of stem cell-based therapies, a major number of clinical trials have not yet acquired full regulatory approvals for validation as stem cell therapies. To date, the most established stem cell treatment is bone marrow transplants to treat blood and immune system disorders ( 1 , 6 , 7 ).

In this review, the advances and challenges for the development of stem-cell-based therapies are described, with focus on the use of stem cells in dentistry in addition to the advances reached in regenerative treatment modalities in several diseases. The limitations of these treatments and ongoing challenges in the field are also discussed while shedding light on the ethical and regulatory challenges in translating autologous stem cell-based interventions, into safe and effective therapies.

Stem cell-based therapies

Stem cell-based therapies are defined as any treatment for a disease or a medical condition that fundamentally involves the use of any type of viable human stem cells including embryonic stem cells (ESCs), iPSCs and adult stem cells for autologous and allogeneic therapies ( 8 ). Stem cells offer the perfect solution when there is a need for tissue and organ transplantation through their ability to differentiate into the specific cell types that are required for repair of diseased tissues.

However, the complexity of stem cell-based therapies often leads researchers to search for stable, safe and easily accessible stem cells source that has the potential to differentiate into several lineages. Thus, it is of utmost importance to carefully select the type of stem cells that is suitable for clinical application ( 7 , 9 ).

Stem cells hierarchy

There are mainly three types of stem cells. All three of them share the significant property of self-renewal in addition to a unique ability to differentiate. However, it should be noted that stem cells are not homogeneous, but rather exist in a developmental hierarchy ( 10 ). The most basic and undeveloped of stem cells are the totipotent stem cells. These cells are capable of developing into a complete embryo while forming the extra-embryonic tissue at the same time. This unique property is brief and starts with the fertilization of the ovum and ends when the embryo reaches the four to eight cells stage. Following that cells undergo subsequent divisions until reaching the blastocyst stage where they lose their totipotency property and assume a pluripotent identity where cells are only capable of differentiating into every embryonic germ layer (ectoderm, mesoderm and endoderm). Cells of this stage are termed “embryonic stem cells” and are obtained by isolation from the inner cell mass of the blastocyst in a process that involves the destruction of the forming embryo. After consecutive divisions, the property of pluripotency is lost and the differentiation capability becomes more lineage restricted where the cells become multipotent meaning that they can only differentiate into limited types of cells related to the tissue of origin. This is the property of “adult stem cells”, which helps create a state of homeostasis throughout the lifetime of the organism. Adult stem cells are present in a metabolically quiescent state in almost all specialized tissues of the body, which includes bone marrow and oral and dental tissues among many others ( 11 ).

Many authors consider adult stem cells the gold standard in stem cell-based therapies ( 12 , 13 ). Adult stem cells demonstrated signs of clinical success especially in hematopoietic transplants ( 14 , 15 ). In contrast to ESCs, adult stem cells are not subjected to controversial views regarding their origin. The fact that ESCs derivation involves destruction of human embryos renders them unacceptable for a significant proportion of the population for ethical and religious convictions ( 16 - 18 ).

Turning point in stem cell research

It was in 2006 when Shinya Yamanka achieved a scientific breakthrough in stem cell research by succeeding in generating cells that have the same properties and genetic profile of ESCs. This was achieved via the transient over-expression of a cocktail of four transcription factors; OCT4, SOX2, KLF4 and MYC in, fully differentiated somatic cells, namely fibroblasts ( 19 , 20 ). These cells were called iPSCs and has transformed the field of stem cell research ever since ( 21 ). The most important feature of these cells is their ability to differentiate into any of the germ layers just like ESCs precluding the ethical debate surrounding their use. The development of iPSCs technology has created an innovative way to both identify and treat diseases. Since they can be generated from the patient’s own cells, iPSCs thus present a promising potential for the production of pluripotent derived patient-matched cells that could be used for autologous transplantation. True these cells symbolize a paradigm shift since they enable researchers to directly observe and treat relevant patient cells; nevertheless, a number of challenges still need to be addressed before iPSCs-derived cells can be applied in cell therapies. Such challenges include; the detection and removal of incompletely differentiated cells, addressing the genomic and epigenetic alterations in the generated cells and overcoming the tumorigenicity of these cells that could arise on transplantation ( 22 ).

Therapeutic translation of stem cell research

With the rapid increase witnessed in stem cell basic research over the past years, the relatively new research discipline “Translational Research” has evolved significantly building up on the outcomes of basic research in order to develop new therapies. The clinical translation pathway starts after acquiring the suitable regulatory approvals. The importance of translational research lies in it’s a role as a filter to ensure that only safe and effective therapies reach the clinic ( 23 ). It bridges the gap from bench to bed. Currently, some stem cell-based therapies utilizing adult stem cells are clinically available and mainly include bone marrow transplants of hematopoietic stem cells and skin grafts for severe burns ( 23 ). To date, there are more than 3,000 trials involving the use of adult stem cells registered in WHO International Clinical Trials Registry. Additionally, initial trials involving the new and appealing iPSCs based therapies are also registered. In fact, the first clinical attempt employing iPSCs reported successful results in treating macular degeneration ( 24 ). Given the relative immaturity in the field of cellular therapy, the outcomes of such trials shall facilitate the understanding of the timeframes needed to achieve successful therapies and help in better understanding of the diseases. However, it is noteworthy that evaluation of stem cell-based therapies is not an easy task since transplantation of cells is ectopic and may result in tumor formation and other complications. This accounts for the variations in the results reported from previous reports. The following section discusses the published data of some of the most important clinical trials involving the use of different types of stem cells both in medicine and in dentistry.

Stem cell-based therapy for neurodegenerative diseases

The successful generation of neural cells from stem cells in vitro paved the way for the current stem cell-based clinical trials targeting neurodegenerative diseases ( 25 , 26 ). These therapies do not just target detaining the progression of irrecoverable neuro-degenerative diseases like Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), but are also focused on completely treating such disorders.

Parkinson’s disease (PD)

PD is characterized by a rapid loss of midbrain dopaminergic neurons. The first attempt for using human ESC cells to treat PD was via the generation of dopaminergic-like neurons, later human iPSCs was proposed as an alternative to overcome ESCs controversies ( 27 ). Both cells presented hope for obtaining an endless source of dopaminergic neurons instead of the previously used fetal brain tissues. Subsequently, protocols that mimicked the development of dopaminergic neurons succeeded in generating dopaminergic neurons similar to that of the midbrain which were able to survive, integrate and functionally mature in animal models of PD preclinically ( 28 ). Based on the research presented by different groups; the “Parkinson’s Global Force” was formed which aimed at guiding researchers to optimize their cell characterization and help promote the clinical progress toward successful therapy. Recently, In August 2018, Shinya Yamanka initiated the first approved clinical trial to treat PD using iPSCs. Seven patients suffering from moderate PD were recruited ( 29 ). Donor matched allogeneic cells were used to avoid any genetic influence of the disease. The strategy behind the trial involved the generation of dopaminergic progenitors followed by surgical transplantation into the brains of patients by a special device. In addition, immunosuppressant medications were given to avoid any adverse reaction. Preliminary results so far revealed the safety of the treatment.

MS is an inflammatory and neurodegenerative autoimmune disease of the central nervous system. Stem cell-based therapies are now exploring the possibility of halting the disease progression and reverse the neural damage. A registered phase 1 clinical trial was conducted by the company Celgene TM in 2014 using placental-derived mesenchymal stem cells (MSCs) infusion to treat patients suffering from MS ( 30 ). This trial was performed at 6 centers in the United States and 2 centers in Canada and included 16 patients. Results demonstrated that cellular infusions were safe with no signs of paradoxical aggravation. However, clinical responses from patients indicated that the cellular treatment did not improve the MS condition ( 31 ). For the last decade immunoablative therapy demonstrated accumulative evidence of inducing long-term remission and improvement of disability caused by MS. This approach involves the replacement of the diseased immune system through administration of high-dose immunosuppressive therapy followed by hematopoietic stem cells infusion ( 32 ). However, immunoablation strategies demonstrated several complications such as infertility and neurological disabilities. A number of randomized controlled trials are planned to address these concerns ( 32 ). Currently, new and innovative stem cell-based therapies for MS are only in the initial stages, and are based on different mechanisms exploring the possibility of replacing damaged neuronal tissue with neural cells derived from iPSCs however, the therapeutic potential of iPSCs is still under research ( 33 ).

ALS is a neurodegenerative disease that causes degeneration of the motor neurons which results in disturbance in muscle performance. The first attempt to treat ALS was through the transplantation of MSCs in a mouse model. The outcomes of this experiment were promising and resulted in a decrease of the disease manifestations and thus providing proof of principal ( 34 ). Based on these results, several planned/ongoing clinical trials are on the way. These trials mainly assess the safety of the proposed concept and have not proved clinical success to date. Notably, while pre-clinical studies have reported that cells derived from un-diseased individuals are superior to cells from ALS patients; most of the clinical trials attempted have employed autologous transplantation. This information may account for the absence of therapeutic improvement reported ( 35 ).

Spinal cord injury

Other neurologic indications for the use of stem cells are spinal cord injuries. Though the transplantation of different forms of neural stem cells and oligo-dendrocyte progenitors has led to growth in the axons in addition to neural connectivity which presents a possibility for repair ( 36 ), proof of recovered function has yet to be established in stringent clinical trials. Nevertheless, Japan has recently given approval to stem-cell treatment for spinal-cord injuries. This approval was based on clinical trials that are yet to be published and involves 13 patients, who are suffering from recent spinal-cord injury. The Japanese team discovered that injection of stem cells isolated from the patients’ bone marrow aided in regaining some lost sensation and mobility. This is the first stem cell-based therapy targeting spinal-cord injuries to gain governmental approval to offer to patients ( 37 ).

Stem cell-based therapies for ocular diseases

A huge number of the currently registered clinical trials for stem cell-based therapies target ocular diseases. This is mainly due to the fact that the eye is an immune privileged site. Most of these trials span various countries including Japan, China, Israel, Korea, UK, and USA and implement allogeneic ESC lines ( 35 , 36 ). Notably, the first clinical trial to implement the use autologous iPSCs-derived retinal cells was in Japan which followed the new regulatory laws issued in 2014 by Japan’s government to regulate regenerative medicine applications. Two patients were recruited in this trial, the first one received treatment for macular degeneration using iPSCs-generated retinal cell sheet ( 37 ). After 1 year of follow-up, there were no signs of serious complications including abnormal proliferation and systemic malignancy. Moreover, there were no signs of rejection of the transplanted retinal epithelial sheet in the second year follow-up. Most importantly, the signs of corrected visual acuity of the treated eye were reported. These results were enough to conclude that iPSCs-based autologous transplantation was safe and feasible ( 38 ). It is worthy to mention that the second patient was withdrawn from the study due to detectable genetic variations the patient’s iPSCs lines which was not originally present in the patient’s original fibroblasts. Such alterations may jeopardize the overall safety of the treatment. The fact that this decision was taken, even though the performed safety assays did not demonstrate tumorgenicity in the iPSCs-derived retinal pigment epithelium (RPE) cells, indicates that researchers in the field of iPSCs have full awareness of the importance of safety issues ( 39 ).

Stem cell-based therapies for treatment of diabetes

Pancreatic beta cells are destructed in type 1 diabetes mellitus, because of disorders in the immune system while in type 2 insulin insufficiency is caused by failure of the beta-cell to normally produce insulin. In both cases the affected cell is the beta cell, and since the pancreas does not efficiently regenerate islets from endogenous adult stem cells, other cell sources were tested ( 38 ). Pluripotent stem cells (PSCs) are considered the cells of choice for beta cell replacement strategies ( 39 ). Currently, there are a few industry-sponsored clinical trials that are registered targeting beta cell replacement using ESCs. These trials revolve around the engraftment of insulin-producing beta cells in an encapsulating device subcutaneously to protect the cells from autoimmunity in patients with type 1 diabetes ( 40 ). The company ViaCyte TM in California recently initiated a phase I/II trial ( {"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}} NCT02239354 ) in 2014 in collaboration with Harvard University. This trial involves 40 patients and employs two subcutaneous capsules of insulin producing beta cells generated from ESCs. The results shall be interesting due to the ease of monitoring and recovery of the transplanted cells. The preclinical studies preceding this trial demonstrated successful glycemic correction and the devices were successfully retrieved after 174 days and contained viable insulin-producing cells ( 41 ).

Stem cells in dentistry

Stem cells have been successfully isolated from human teeth and were studied to test their ability to regenerate dental structures and periodontal tissues. MSCs were reported to be successfully isolated from dental tissues like dental pulp of permanent and deciduous teeth, periodontal ligament, apical papilla and dental follicle ( 42 - 44 ). These cells were described as an excellent cell source owing to their ease of accessibility, their ability to differentiate into osteoblasts and odontoblasts and lack of ethical controversies ( 45 ). Moreover, dental stem cells demonstrated superior abilities in immunomodulation properties either through cell to cell interaction or via a paracrine effect ( 46 ). Stem cells of non-dental origin were also suggested for dental tissue and bone regeneration. Different approaches were investigated for achieving dental and periodontal regeneration ( 47 ); however, assessments of stem cells after transplantation still require extensive studying. Clinical trials have only recently begun and their results are yet to be fully evaluated. However, by carefully applying the knowledge acquired from the extensive basic research in dental and periodontal regeneration, stem cell-based dental and periodontal regeneration may soon be a readily available treatment. To date, there are more than 6,000 clinical trials involving the use of with stem cells, however only a total of 44 registered clinical trials address oral diseases worldwide ( 48 ). Stem cell-based clinical trials with reported results targeting the treatment of oral disease are discussed below.

Dental pulp regeneration

The first human clinical study using autologous dental pulp stem cells (DPSCs) for complete pulp regeneration was reported by Nakashima et al. in 2017 ( 49 ). This pilot study was based on extensive preclinical studies conducted by the same group ( 50 ). Patients with irreversible pulpitis were recruited and followed up for 6 months following DPSCs’ transplantation. Granulocyte colony-stimulating factor was administered to induce stem cell mobilization to enrich the stem cell populations. The research team reported that the use of DPSCs seeded on collagen scaffold in molars and premolars undergoing pulpectomy was safe. No adverse events or toxicity were demonstrated in the clinical and laboratory evaluations. Positive electric pulp testing was obtained after cell transplantation in all patients. Moreover, magnetic resonance imaging of the de - novo tissues formed in the root canal demonstrated similar results to normal pulp, which indicated successful pulp regeneration. A different group conducted a clinical trial that recruited patients diagnosed with necrotic pulp. Autologous stem cells from deciduous teeth were employed to induce pulp regeneration ( 51 ). Follow-up of the cases after a year from the intervention reported evidence of pulp regeneration with vascular supply and innervation. In addition, no signs of adverse effects were observed in patients receiving DPSCs transplantation. Both trials are proceeding with the next phases, however the results obtained are promising.

Periodontal tissue regeneration

Aimetti et al. performed a study which included eleven patients suffering from chronic periodontitis and have one deep intra bony defect in addition to the presence of one vital tooth that needs extraction ( 52 ). Pulp tissue was passed through 50-µm filters in presence of collagen sponge scaffold and was followed by transplantation in the bony defects caused by periodontal disease. Both clinical and radiographic evaluations confirmed the efficacy of this therapeutic intervention. Periodontal examination, attachment level, and probe depth showed improved results in addition to significant stability of the gingival margin. Moreover, radiographic analysis demonstrated bone regeneration.

Regeneration of mandibular bony defects

The first clinical study using DPSCs for oro-maxillo-facial bone regeneration was conducted in 2009 ( 53 ). Patients in this study suffered from extreme bone loss following extraction of third molars. A bio-complex composed of DPSCs cultured on collagen sponge scaffolds was applied to the affected sites. Vertical repair of the damaged area with complete restoration of the periodontal tissue was demonstrated six months after the treatment. Three years later, the same group published a report evaluating the stability and quality of the regenerated bone after DPSCs transplantation ( 54 ). Histological and advanced holotomography demonstrated that newly formed bone was uniformly vascularized. However, it was of compact type, rather than a cancellous type which is usually the type of bone in this region.

Stem cells for treatment of Sjögren’s syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease marked by dry mouth and eyes. A novel therapeutic approach for SS. utilizing the infusion of MSCs in 24 patients was reported by Xu et al. in 2012 ( 55 ). The strategy behind this treatment was based on the immunologic regulatory functions of MSCs. Infused MSCs migrated toward the inflammatory sites in a stromal cell-derived factor-1-dependent manner. Results reported from this clinical trial demonstrated suppressed autoimmunity with subsequent restoration of salivary gland secretion in SS patients.

Stem cells and tissue banks

The ability to bank autologous stem cells at their most potent state for later use is an essential adjuvant to stem cell-based therapies. In order to be considered valid, any novel stem cell-based therapy should be as effective as the routine treatment. Thus, when appraising a type of stem cells for application in cellular therapies, issues like immune rejection must be avoided and at the same time large numbers of stem cells must be readily available before clinical implementation. iPSCs theoretically possess the ability to proliferate unlimitedly which pose them as an attractive source for use in cell-based therapies. Unlike, adult stem cells iPSCs ability to propagate does not decrease with time ( 22 ). Recently, California Institute for Regenerative Medicine (CIRM) has inaugurated an iPSCs repository to provide researchers with versatile iPSCs cell lines in order to accelerate stem cell treatments through studying genetic variation and disease modeling. Another important source for stem cells banking is the umbilical cord. Umbilical cord is immediately cryopreserved after birth; which permits stem cells to be successfully stored and ready for use in cell-based therapies for incurable diseases of a given individuals. However, stem cells of human exfoliated deciduous teeth (SHEDs) are more attractive as a source for stem cell banking. These cells have the capacity to differentiate into further cell types than the rest of the adult stem cells ( 56 ). Moreover, procedures involving the isolation and cryopreservation of these cells are un-complicated and not aggressive. The most important advantage of banking SHEDs is the insured autologous transplant which avoids the possibility of immune rejection ( 57 ). Contrary to cord blood stem cells, SHEDs have the ability to differentiate into connective tissues, neural and dental tissues ( 58 ) Finally, the ultimate goal of stem cell banking, is to establish a repository of high-quality stem cell lines derived from many individuals for future use in therapy.

Current regulatory guidelines for stem cell-based therapies

With the increased number of clinical trials employing stem cells as therapeutic approaches, the need for developing regulatory guidelines and standards to ensure patients safety is becoming more and more essential. However, the fact that stem cell therapy is rather a new domain makes it subject to scientific, ethical and legal controversies that are yet to be regulated. Leading countries in the field have devised guidelines serving that purpose. Recently, the Food and Drug Administration (FDA) has released regulatory guidelines to ensure that these treatments are safe and effective ( 59 ). These guidelines state that; treatments involving stem cells that have been minimally manipulated and are intended for homogeneous use do not require premarket approval to come into action and shall only be subjected to regulatory guidelines against disease transmission. In 2014, a radical regulatory reform in Japan occurred with the passing of two new laws that permitted conditional approval of cell-based treatments following early phase clinical trials on the condition that clinical safety data are provided from at least ten patients. These laws allow skipping most of the traditional criteria of clinical trials in what was described as “fast track approvals” and treatments were classified according to risk ( 60 ). To date, the treatments that acquired conditional approval include those targeting; spinal-cord injury, cardiac disease and limb ischemia ( 61 ). Finally, regulatory authorities are now demanding application of standardization and safety regulations protocols for cellular products, which include the use of Xeno-free culture media, recombinant growth factors in addition to “Good Manufacturing Practice” (GMP) culture supplies.

Challenges & ethical issues facing stem cell-based therapies

Stem cell-based therapies face many obstacles that need to be urgently addressed. The most persistent concern is the ethical conflict regarding the use of ESCs. As previously mentioned, ESCs are far superior regarding their potency; however, their derivation requires destruction human embryos. True, the discovery of iPSCs overcame this concern; nevertheless, iPSCs themselves currently face another ethical controversy of their own which addresses their unlimited capacity of differentiation with concerns that these cells could one day be applied in human cloning. The use of iPSCs in therapy is still considered a high-risk treatment modality, since transplantation of these cells could induce tumor formation. Such challenge is currently addressed through developing optimized protocols to ensure their safety in addition to developing global clinical-grade iPSCs cell lines before these cells are available for clinical use ( 61 ). As for MSCs, these cells have been universally considered safe, however continuous monitoring and prolonged follow-up should be the focus of future research to avoid the possibility of tumor formation after treatments ( 62 ). Finally, it could be postulated that one of the most challenging ethical issues faced in the field of stem cell-based therapies at the moment, is the increasing number of clinics offering unproven stem cell-based treatments. Researchers are thus morally obligated to ensure that ethical considerations are not undermined in pursuit of progress in clinical translation.

Conclusions

Stem cell therapy is becoming a tangible reality by the day, thanks to the mounting research conducted over the past decade. With every research conducted the possibilities of stem cells applications increased in spite of the many challenges faced. Currently, progress in the field of stem cells is very promising with reports of clinical success in treating various diseases like; neurodegenerative diseases and macular degeneration progressing rapidly. iPSCs are conquering the field of stem cells research with endless possibilities of treating diseases using patients own cells. Regeneration of dental and periodontal tissues using MSCs has made its way to the clinic and soon enough will become a valid treatment. Although, challenges might seem daunting, stem cell research is advancing rapidly and cellular therapeutics is soon to be applicable. Fortunately, there are currently tremendous efforts exerted globally towards setting up regulatory guidelines and standards to ensure patients safety. In the near future, stem cell-based therapies shall significantly impact human health.

Acknowledgments

Funding: None.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/ .

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/sci-2020-001 ). The author has no conflicts of interest to declare.

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The efficiency of stem cell differentiation into functional beta cells for treating insulin-requiring diabetes: Recent advances and current challenges

• Published: 10 May 2024

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• Yunfei Luo 1 ,
• Peng Yu 1 &
• Jianping Liu 1  

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In recent years, the potential of stem cells (SCs) to differentiate into various types of cells, including β-cells, has led to a significant boost in development. The efficiency of this differentiation process and the functionality of the cells post-transplantation are crucial factors for the success of stem cell therapy in diabetes. Herein, this article reviews the current advances and challenges faced by stem cell differentiation into functional β-cells for diabetes treatment. In vitro, researchers have sought to enhance the differentiation efficiency of functional β-cells by mimicking the normal pancreatic development process, using gene manipulation, pharmacological and culture conditions stimulation, three-dimensional (3D) and organoid culture, or sorting for functional β-cells based on mature islet cell markers. Furthermore, in vivo studies have also looked at suitable transplantation sites, the enhancement of the transplantation microenvironment, immune modulation, and vascular function reconstruction to improve the survival rate of functional β-cells, thereby enhancing the treatment of diabetes. Despite these advancements, developing stem cells to produce functional β-cells for efficacious diabetes treatment is a continuous research endeavor requiring significant multidisciplinary collaboration, for the stem-cell-derived beta cells to evolve into an effective cellular therapy.

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Abbreviations.

insulin-producing cells

embryonic stem cells

nuclear transfer embryonic stem cells

cord blood stem cells

Umbilical cord blood mesenchymal stem cells

human amniotic fluid stem cells

adipose tissue-derived stem cells

islet-like cell aggregates

Muscle-derived stem/progenitor cells

induced pluripotent stem cells

human amniotic epithelial cells

human embryonic stem cell

human marrow stromal cells

epidermal growth factor

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This review was supported by grants from the National Nature Science Foundation of China (82160162, 81760150) and the key project of Jiangxi Provincial Natural Science Foundation (20202ACBL206008).

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Yunfei Luo, Peng Yu & Jianping Liu

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Luo, Y., Yu, P. & Liu, J. The efficiency of stem cell differentiation into functional beta cells for treating insulin-requiring diabetes: Recent advances and current challenges. Endocrine (2024). https://doi.org/10.1007/s12020-024-03855-8

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Stem cells provide new insight into genetic pathway of childhood cancer

Scientists have discovered a new insight into the genetic pathway of childhood cancer, offering new hope for tailored treatments.

Researchers from the University of Sheffield have created a stem cell model designed to investigate the origins of neuroblastoma, a cancer primarily affecting babies and young children.

Neuroblastoma is the most common childhood tumour occurring outside the brain, affecting the lives of approximately 600 children in the European Union and the United Kingdom each year.

Until now, studying genetic changes and their role in neuroblastoma initiation has been challenging due to the lack of suitable laboratory methods. A new model developed by researchers at the University of Sheffield, in collaboration with the St Anna Children's Cancer Research Institute in Vienna, replicates the emergence of early neuroblastoma cancer-like cells, giving an insight into the genetic pathway of the disease.

The research, published in Nature Communications , sheds light on the intricate genetic pathways which initiate neuroblastoma. The international research team found that specific mutations in chromosomes 17 and 1, combined with overactivation of the MYCN gene, play a pivotal role in the development of aggressive neuroblastoma tumours.

Childhood cancer is often diagnosed and detected late, leaving researchers with very little idea of the conditions that led to tumour initiation, which occurs very early during fetal development. In order to understand tumour initiation, models which recreate the conditions that lead to the appearance of a tumour are vital.

The formation of neuroblastoma usually starts in the womb when a group of normal embryonic cells called 'trunk neural crest (NC)' become mutated and cancerous.

In an interdisciplinary effort spearheaded by stem cell expert Dr Ingrid Saldana from the University of Sheffield's School of Biosciences and computational biologist Dr Luis Montano from the St Anna Children's Cancer Research Institute in Vienna, the new study found a way in which to use human stem cells to grow trunk NC cells in a petri dish.

These cells carried genetic changes often seen in aggressive neuroblastoma tumours. Using genomics analysis and advanced imaging techniques, the researchers found that the altered cells started behaving like cancer cells and looked very similar to the neuroblastoma cells found in sick children.

The findings offer new hope for the creation of tailored treatments that specifically target the cancer while minimising the adverse effects experienced by patients from existing therapies.

Dr Anestis Tsakiridis, from the University of Sheffield's School of Biosciences and lead author of the study, said: "Our stem cell-based model mimics the early stages of aggressive neuroblastoma formation, providing invaluable insights into the genetic drivers of this devastating childhood cancer. By recreating the conditions that lead to tumour initiation, we will be able to understand better the mechanisms underpinning this process and thus design improved treatment strategies in the longer term.

"This is very important as survival rates for children with aggressive neuroblastoma are poor and most survivors suffer from side effects linked to the harsh treatments currently used, which include potential hearing, fertility and lung problems."

Dr. Florian Halbritter, from St. Anna Children's Cancer Research Institute and second lead author of the study, said: "This was an impressive team effort, breaching geographic and disciplinary boundaries to enable new discoveries in childhood cancer research."

This research supports the University of Sheffield's cancer research strategy. Through the strategy, the University aims to prevent cancer-related deaths by undertaking high quality research, leading to more effective treatments, as well as methods to better prevent and detect cancer and improve quality of life.

• Lung Cancer
• Breast Cancer
• Skin Cancer
• Brain Tumor
• Prostate Cancer
• Colon Cancer
• Stem cell treatments
• Cervical cancer
• Colorectal cancer
• Breast cancer
• Prostate cancer

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Materials provided by University of Sheffield . Note: Content may be edited for style and length.

Journal Reference :

• Ingrid M. Saldana-Guerrero, Luis F. Montano-Gutierrez, Katy Boswell, Christoph Hafemeister, Evon Poon, Lisa E. Shaw, Dylan Stavish, Rebecca A. Lea, Sara Wernig-Zorc, Eva Bozsaky, Irfete S. Fetahu, Peter Zoescher, Ulrike Pötschger, Marie Bernkopf, Andrea Wenninger-Weinzierl, Caterina Sturtzel, Celine Souilhol, Sophia Tarelli, Mohamed R. Shoeb, Polyxeni Bozatzi, Magdalena Rados, Maria Guarini, Michelle C. Buri, Wolfgang Weninger, Eva M. Putz, Miller Huang, Ruth Ladenstein, Peter W. Andrews, Ivana Barbaric, George D. Cresswell, Helen E. Bryant, Martin Distel, Louis Chesler, Sabine Taschner-Mandl, Matthias Farlik, Anestis Tsakiridis, Florian Halbritter. A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations . Nature Communications , 2024; 15 (1) DOI: 10.1038/s41467-024-47945-7

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Supporting stem cell research.

Today, millions of Americans suffer from conditions like Alzheimer’s Parkinson’s and heart disease. And while we don’t know exactly what stem cell research will yield, scientists tell us that this research has the potential to help treat or cure these and many other diseases and conditions.

That’s why President Obama supports responsible stem cell research and it’s why we’re pleased with a court decision that paves the way for stem cell research to continue.  Earlier today, a court ruled that a lawsuit challenging the federal government’s ability to support stem cell research was unlikely to succeed and allowed federally supported stem cell research to continue.

The ruling was a victory for scientists and the patients who will benefit from their work. And the ruling will help ensure our nation remains at the forefront of scientific and medical research and innovation.  As President Obama said tonight to the students of Miami Dade College at their commencement   , “America will only be as strong as our pursuit of scientific research and our leadership in technology and innovation.”

Stem cell research has the potential to cure diseases that have touched virtually every American family. We’re committed to realizing this potential and supporting responsible research that could develop new treatments, improve public health and deliver relief to patients in America and around the world. 

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• Open access
• Published: 20 May 2024

Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation

• Hyun Sung Park 1 ,
• Byung-Chul Lee 2 , 3 ,
• Dong-Hoon Chae 1 ,
• Aaron Yu 1 ,
• Jae Han Park 1 ,
• Jiyoung Heo 1 ,
• Myoung Hee Han 1 ,
• Keonwoo Cho 1 ,
• Joong Won Lee 4 ,
• Ji-Won Jung 4 ,
• Cynthia E. Dunbar 5 ,
• Mi-Kyung Oh 1 &
• Kyung-Rok Yu 1   na1  

Stem Cell Research & Therapy volume  15 , Article number:  145 ( 2024 ) Cite this article

Metrics details

Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated.

In the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs.

Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs.

In conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.

According to the 2021 report from the World Health Organization (WHO), despite decades of knowledge regarding health risks, tobacco continues to account for more than 8 million deaths per year worldwide [ 1 ]. Cigarette smoke (CS) contains more than 4,000 toxic chemicals and carcinogens, which contributes to a wide variety of diseases, including cancer, heart disease, lung damage, stroke, and diabetes, resulting in premature death [ 2 , 3 ]. CS induces cytotoxic DNA damage that leads to tissue damage and inflammation. Among the various target tissues of interest, there is epidemiologic evidence that CS can impact bone marrow function, most notably a strong association with clonal hematopoiesis, with expansion of somatically-mutated clones resulting in a higher risk of hematologic cancers as well as systemic hyperinflammation [ 4 , 5 , 6 ]. Murine studies have suggested an impact on both hematopoietic stem and progenitor cells as well as bone marrow (BM) niche elements, including proliferative exhaustion of HSPCs, changes in mesenchymal stromal cells (MSCs), and induction of extramedullary hematopoiesis [ 4 ]. CS also has been shown to impact outcomes once HSPC malignant transformation has occurred, with shorter remissions and subsequent survival [ 7 ].

In the BM niche microenvironment, mesenchymal stem cells (MSCs) play a pivotal role in regulating self-renewal, survival and differentiation of resident HSPCs through direct contact or paracrine effects [ 8 , 9 ]. Additionally, MSCs have been developed as a critical tool for maintaining or expanding HSPCs ex vivo prior to transplantation, while preserving their engraftment potential [ 10 , 11 ]. Cotransplantation of MSCs together with HSPCs facilitates a reduction in the harmful inflammatory responses and contributes to successful engraftment and hematopoietic recovery [ 12 ]. However, recent studies suggest that CS can alter multiple characteristics of MSCs, including their ability to support HSPCs [ 13 , 14 ]. Exposure to CS increases the expression of genes in MSCs that stimulate the proliferation of murine HSPCs in in vitro coculture studies. This exposure potentially results in HSPC exhaustion in vivo, accompanied by impaired engraftment efficiency and a decrease in the absolute number of HSPCs [ 11 ]. Nevertheless, there is limited information regarding the pathways impacted by cigarette smoking extract (CSE) on human MSCs and HSPCs.

The production of reactive oxygen species (ROS) by smoking is closely related to the regulation of MSC function. Studies have shown that exposure to ROS derived from CS impairs the regenerative potential of MSCs, reducing their ability to effectively contribute to tissue repair processes [ 15 ]. Moreover, it has been reported that increased levels of ROS can negatively impact the function and engraftment capacity of HSPCs [ 16 ]. These findings suggest that MSCs exposed to CS have the potential to regulate hematopoietic system via ROS generation. ROS have been identified as factors that trigger apoptosis in multiple immune cells, such as neutrophils and macrophages. In addition, recent studies have suggested that CSE-induced ROS production in human bronchial epithelial cells and monocyte cells activate the nucleotide-binding domain-like receptor protein-3 (NLRP3) inflammasome, leading to pyroptosis, another form of cellular degeneration [ 17 , 18 , 19 , 20 ]. Although ROS and NLRP3 are associated with apoptosis and pyroptosis in a variety of cell types, the relationship between ROS and NLRP3 in MSCs within the context of hematopoietic niche is not fully understood.

In the present study, we comprehensively investigated the in vitro and in vivo deleterious effects of 3R4F, a reference compound for CSE, on the human HSPC-supportive function of MSCs. We asked whether exposure to CSE could reduce the ability of MSCs to support engraftment of transplanted human HSPCs in a preclinical immunodeficient mouse model. Additionally, we investigated potential pathways involved in bone marrow niche dysfunction, specifically production of reactive oxygen species (ROS) with downstream activation of the NLRP3 inflammasome in MSCs.

Cigarette smoke extract (CSE) preparation

A conventional combustion reference cigarette (3R4F) was obtained from the University of Kentucky (Lexington, KY, USA). Cigarette smoke extract (CSE) was prepared according to ISO/TR 19478-2:2015(en) and Health Canada Method T-115. Briefly, five 3R4F cigarettes were continuously smoked, and CSE were prepared by bubbling smoke into 35 mL of phosphate buffered saline (PBS), which contained approximately 20 µg/mL nicotine. The obtained CSE was diluted as indicated in the study (% v/v).

Isolation of human CD34 + cells from human umbilical cord blood

Human CD34 + cells were isolated from human umbilical cord blood as previously described [ 21 ]. Briefly, human umbilical cord blood (UCB) was mixed with HetaSep™ solution (STEMCELL Technologies, Vancouver, BC, Canada) at a 5:1 ratio and incubated for 1 h at room temperature. The human mononuclear cells (hMNCs) were isolated from supernatants by density-gradient centrifugation (Ficoll-Paque PLUS, GE Healthcare, Chicago, IL, USA). CD34 + hematopoietic stem and progenitor cells (HSPCs) were enriched from hMNCs via magnetic activated cell sorting using human CD34 + MicroBead Kit (Miltenyi Biotec, Bergisch Gladbach, Germany) according to the manufacturer’s instructions.

Xenotransplantation mouse model

NOD-scid-IL2Rγc −/− (NSG) mice were purchased from Jackson Laboratory (Bar Harbor, ME, USA) and housed in a specific pathogen-free facility. Eight-week-old female NSG mice were purchased and housed in a specific pathogen-free facility. For systemic CSE administration, 3R4F (0.5 mL of CSE/kg) was injected intravenously for 4 days, and the control group was injected with 100 µL PBS. To investigate the effect of CSE on the MSC niche, hUCB-derived CD34 + HSPCs were cocultured with CSE-treated hMSCs for 3 days and enriched by magnetic activated cell sorting using anti-CD34-conjugated microbeads (Miltenyi Biotec). For NSG bone marrow ablation, busulfan (Sigma‒Aldrich, St. Louis, MO, USA) was dissolved in dimethyl sulfoxide (DMSO, 16 mg/mL) and diluted with PBS at 1:4 ratio. Diluted busulfan was intraperitoneally injected into NSG mice (20 mg/kg). The next day, 5 × 10 4 CD34 + cells were suspended in 100 µL PBS and infused into the NSG mice via intravenous injection.

Analysis of engraftment

Mouse peripheral blood (mPB) samples were collected from the retro-orbital plexus or tail vein 8 weeks after CD34 + HSPC transplantation. At 15 weeks after transplantation, the mice were euthanized by CO 2 , and bone marrow (mBM) and mPB were harvested. mBM was flushed from the femur in RPMI with 10% FBS. Red blood cells were lysed from the PB and BM samples using RBC lysis buffer (Biolegend, San Diego, CA). Single cell suspensions of mPB and mBM were labeled with anti-mouse CD45 (#552848, BD Biosciences), anti-human CD45 (#563879, BD Biosciences), anti-human CD3 (#555341, BD Biosciences), anti-human CD14 (#557831, BD Biosciences), anti-human CD20 (#555623, BD Biosciences), and anti-human CD33 (#564588, BD Biosciences) antibodies and run on an Attune NxT flow cytometer (Thermo Fisher Scientific, Waltham, MA, USA), with analysis by FlowJo V.10 software (BD Biosciences, Franklin Lakes, NJ, USA). To exclude dead cells, 7-AAD (#559925, BD Biosciences) was used.

Isolation and culture of mouse bone marrow (BM)-MSCs

All animal experiments were approved and conducted in accordance with the Institutional Animal Care and Use Committee (KCDC-029-20-2 A) of the Korea Centers for Disease Control and Prevention. Five-week-old female ICR mice (n = 20) were grouped randomly: Control and 3R4F. Mice in the experimental groups were intravenously injected with 6.25% 3R4F in a total volume of 200 µL PBS, and the control group was injected with 200 µL PBS. All mice received 2 cycles of the injection for 5 consecutive days per week. After euthanasia, mouse BM-MSCs were isolated from the femur and tibia by flushing with DMEM (Gibco, Grand Island, NY, USA). Cells were washed with PBS, and cultured in DMEM supplemented with 10% FBS (Gibco), 1% GlutaMAX (Gibco), 1% antibiotic/antimycotic solution (Gibco), 25 µg/mL EGF (PeproTech), 50 ng/mL bFGF (PeproTech) at 37 °C with 5% CO 2 .

Ex vivo hematopoietic stem cell and progenitor cell (HSPC) expansion analysis

CD34 + HSPCs were enriched from human UCB as mentioned above. Ex vivo HSPC expansion analysis was conducted as previously described [ 21 ]. Briefly, mBM-MSCs or hMSCs were treated with 10 µg/mL Mitomycin C for 1 h and seeded at density of 1 × 10 5 cells per well in a 12-well plate. 1 × 10 4 of CD34 + HSPCs were cocultured with or without mBM-MSCs or hMSCs (MSCs: HSPCs = 10:1). On day 3 of expansion, HSPCs were labeled with human monoclonal antibodies against CD45 (#560178, BD Biosciences), CD34 (#562577, BD Biosciences), and CD90 (#555595, BD Biosciences), and measured with a flow cytometer and analyzed by FlowJo V.10 software (BD Biosciences).

Human Wharton’s jelly-derived mesenchymal stem cells preparation and culture

The human Wharton’ jelly-derived mesenchymal stem cells (hMSCs) were isolated and cultured as previously described [ 21 ]. Briefly, hMSCs were cultured in DMEM (Gibco) supplemented with 10% FBS (Tissue Culture Biologicals), 1% GlutaMAX (Gibco), 1% antibiotic/antimycotic solution (Gibco), 25 ng/mL EGF (PeproTech), and 50 ng/mL bFGF (PeproTech) in a humidified atmosphere containing 5% CO 2 at 37 °C. Cells were passaged every 3–4 days using 0.05% trypsin/ EDTA. The cells were pretreated with or without N-acetyl cysteine (NAC; 5 mM; Sigma‒Aldrich) or MCC950 (10 µM; Sigma‒Aldrich) before 3R4F treatment.

RNA isolation and sequencing (RNA-seq)

RNA sequencing (RNA-seq) was performed by Theragen Bio (Seongnam, South Korea) using Illumina technology as previously described, with modifications [ 22 ]. Total RNA was extracted and purified from hMSCs incubated with or without 5% 3R4F using TRIzol reagent (Invitrogen, Carlsbad, CA, USA). Libraries were generated using the Illumina TruSeq strand mRNA sample preparation kit (Illumina, San Diego, CA, USA) and sequenced on a NovaSeq 6000 (2 × 150 paired end sequencing, Illumina) according to the manufacturer’s protocol. After removing the adapter sequence and filtering the low-quality reads using an in-house script, the filtered reads were aligned to hg38 using HISAT2. The aligned reads were counted by featureCounts. For differential expression analyses, gene expression for each sample group was quantified with the edgeR R package. Differentially expressed genes (DEGs) in the control and CSE-treated hMSCs were identified based on absolute log2-fold change ≥ 1 and FDR < 0.05. Heatmaps were generated using an in-house script, and clustering analysis was performed using a hierarchical clustering method. Volcano plots of DEGs were generated using ggplot 2 package in R. Data can be found via GEO accession number GSE253105 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE253105 ).

Gene Ontology (GO) and gene set enrichment analysis (GSEA)

Differentially expressed genes were subjected to gene enrichment analysis with the R package clusterProfiler, and gene set enrichment analysis (GSEA) was performed using the Broad GSEA application. The significance of the gene sets was calculated using gene set enrichment analysis (GSEA v3.0, https://www.gsea-msigdb.org/gsea/index.jsp ). The significance of each factor was calculated using Fisher’s exact test.

Pathway analysis

Trimmed DEGs (log2-fold change > 2.4, FDR < 0.05) were used for pathway analysis using QIAGEN’s Ingenuity® Pathway Analysis (IPA®, QIAGEN Redwood City, www.qiagen.com/ingenuity ).

Quantitative real-time PCR

Total RNA was extracted using TRIzol reagent (Invitrogen), and 2 µg of total RNA was converted to cDNA using M-MLV Reverse Transcriptase (Promega, Madison, WI, USA). Real-time PCR was performed using 2×SYBR Green Premix (Enzynomics, Daejeon, South Korea) and measured using a CFX96 real-time system (Bio-Rad Laboratories, Hercules, CA). β-actin was used as the reference gene for normalization. The primer sequences for qRT‒PCR are listed in Additional file 2: Table S1 .

Detection of intracellular reactive oxygen species (ROS)

Intracellular reactive oxygen species (ROS) were detected using the peroxide-sensitive fluorophore 2’,7’-dichlorofluorescin diacetate (DCFDA, Sigma‒Aldrich) as previously described [ 22 ]. hMSCs were incubated with 5% 3R4F for 72 h. After incubation, the cells were washed with PBS and incubated with 10 µM DCFDA in serum-free culture medium for 30 min at 37 °C. The mean DCFDA fluorescence was analyzed using an Attune NxT flow cytometer (Thermo Fisher Scientific).

Oxygen consumption rate (OCR) analysis

The oxygen consumption rate (OCR) was measured with the XFe24 Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA, USA). hMSCs were treated with CSE for 72 h and seeded at a density of 4 × 10 4 cells/well in XFe24 microplates. After 24 h, the growth media were exchanged to Seahorse XF DMEM base medium (Seahorse Bioscience) supplemented with glucose (Sigma‒Aldrich), GlutaMAX (Gibco), and sodium pyruvate (Sigma‒Aldrich). After 30 min of equilibration at 37 °C in a non-CO 2 incubator, basal OCR was measured according to the manufacturer’s protocol.

Colony-forming assay

For methylcellulose colony-forming assays, 500 CSE-treated hMSCs were cocultured with CD34 + HSPCs. After incubation, HSPCs were mixed with complete MethoCult H4434 complete medium (STEMCELL Technologies) and seeded in 35-mm culture dishes. After 14 days, the number of erythroid burst-forming units (BFU-E), granulocyte-macrophage colony forming units (CFU-GM) and granulocyte/erythrocyte/macrophage/megakaryocyte colony forming units (CFU-GEMM) was determined with manual counting under an inverted light microscope (Olympus Corporation, Tokyo, Japan).

Western blot analysis

The cells were harvested and lysed using RIPA buffer with protease inhibitor (Thermo Fisher Scientific), and the protein concentrations were determined by the BCA protein assay (Thermo Fisher Scientific). A total of 40 ug of proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to nitrocellulose membranes as previously described [ 23 ]. Blots were incubated with primary antibodies against NLRP3 (#15101; Cell signaling technology, Danvers, MA, USA), ASC (#67824; Cell signaling technology), pro-IL-1β (sc-32294; 1:1,000 dilution; Santa Cruz Biotechnology, Dallas, TX, USA), cleaved IL-1β (#83186; Cell signaling technology), pro-CASP1 (#3866; Cell signaling technology), cleaved CASP1 (#89332; Cell signaling technology), and GAPDH (sc-32233; Santa Cruz Biotechnology) at the 1:1,000 dilution, followed by an incubation with the secondary antibody conjugated to HRP for 1 h in room temperature. The bands were visualized using SuperSignal West Pico PLUS Chemiluminescent (Thermo Fisher Scientific) and luminescent image analyzer (ChemiDoc XRS + Systems, Bio-Rad Laboratories) at multiple exposure settings. For quantification, ImageJ software (National Institutes of Health) were used to analyzed the bands intensity.

Statistical analysis

All experiments were performed at least in triplicate. Where data were normally distributed, the significance was determined using one-way ANOVA followed by a Holm‒Sidak multiple comparisons test. The data are presented as the mean ± standard deviation. All statistical analyses were performed using GraphPad Prism 8 (GraphPad Software Inc.; San Diego, CA, USA).

3R4F suppresses BM niche function of MSCs in vivo and ex vivo

Previous studies have shown that exposure to cigarette smoke reduces the HSPC pool size [ 11 , 24 ]. We therefore investigated the effects of CSE on human hematopoiesis using xenotransplantation in NSG mice. Human cord blood-derived CD34 + HSPC engraftment as measured by hCD45 + % in PB at week 8 post transplantation was significantly reduced in NSG mice given reference cigarette 3R4F extract intravenously (IV) for 4 days prior to transplantation compared to the control group (Fig.  1 A, B and Additional file 1: Fig. S1 A, B). Next, we examined the impact of more prolonged systemic 3R4F-exposure, administering 3R4F IV 5 days a week for 2 weeks into ICR mice (Fig.  1 C, D). On day 15, the mice were sacrificed, and mBM-MSCs were isolated. They were cultured ex vivo with human CD34 + HSPCs. After coculture for 3 days, the proportion of the more primitive HSPCs (CD34 + CD90 + ) was measured. The 3R4F-treated group showed substantial reduction in the percentage of CD34 + CD90 + HSPCs (Fig.  1 E). Taken together, systemic exposure to CSE deteriorates the HSPC-supporting ability of mBM-MSCs, resulting in a reduction in HSPC engraftment.

Systemic administration of 3R4F suppresses HSC niche function of mBM-MSCs. ( A ) Schematic outline of systemic 3R4F administration and subsequent CD34 + HSPC transplantation in humanized mice. ( B ) Engraftment of human cells was determined from the peripheral blood of 3R4F-treated humanized mice by flow cytometric analysis. Left: representative dot plot images. Right: histogram for repetitive results (n = 4). ( C ) Schematic outline of the isolation of 3R4F-exposed mBM-MSCs and the in vitro BM niche function test. CD34 + cells were isolated from hUCB and cocultured with 3R4F-treated mBM-MSCs. ( D ) Body weight change was measured for 12 days. Body weights were normalized using the weight on Day 1 as the denominator (n = 10 mice/group). ( E ) After 3 days of coculture with 3R4F-exposed mBM-MSCs, the CD34 + CD90 + HSPC population in CD45 + cells was analyzed using flow cytometry. Left: representative dot plot images. Right: histogram for repetitive results (n = 3). Experiments were performed at least three times. Data are presented as the mean ± S.D. (**p < 0.01)

Transcriptomic profiling reveals that 3R4F exposure elevates inflammation, cellular aging, wound repair, and ROS in hMSCs

We further evaluated the impact of 3R4F on human MSCs by performing in vitro viability and metabolic assays. Direct treatment for 48 h with 1–5% 3R4F did not result in significant cellular death in hMSCs, but 5% 3R4F reduced the metabolic activity (Additional file 1: Fig. S2 A, B). Additionally, 5% 3R4F inhibited the migration and increased the adipogenic differentiation of hMSCs (Additional file 1: Fig. S2 C, D). Based on these results, 5% 3R4F was used in subsequent experiments.

RNA sequencing was performed to examine the alteration of the transcriptomic profile of 3R4F-treated hMSCs. The differentially expressed genes (DEG) were visualized using hierarchical clustering and a volcano plot (Fig.  2 A and Additional file 1: Fig. S3 A). Gene Ontology (GO) enrichment analysis identified DEGs that were enriched in the biological processes of defense response, response to wounding, and response to oxidative stress. These processes all fall within the ‘response to stimulus’ upper-category that harbors gene sets related to hMSCs’ physiological responses to CSE (Fig.  2 B and Additional file 1: Fig. S3 B). Gene set enrichment analysis (GSEA) using the gene ontology biological process (GO BP) gene sets identified four significantly upregulated categories in 3R4F-treated hMSCs: inflammatory response, aging, wound healing, and response to oxidative stress gene sets (Fig.  2 C). In inflammatory response, enriched gene sets contained upregulated expression of NLRP3 , IL-1β , and, IL-6 (Fig.  2 D).

Transcriptomic profiles of 3R4F-treated MSCs present changes toward inflammation, cellular aging, and wound repair. hMSCs were treated with 5% 3R4F for 48 h, and gene expression was analyzed. ( A ) Heatmap of differentially expressed gene (DEG) profiles for the control and the 3R4F-treated groups (FDR < 0.05). The data were clustered hierarchically. ( B ) GO enrichment analysis of DEGs was performed using the Panther biological processes database. ( C ) Enrichment plot of inflammatory response, aging, wound healing, and response to oxidative stress using GSEA GO-BP gene sets. ( D ) Heatmaps of the inflammatory response, aging, wound healing, and response to oxidative stress using GSEA GO-BP gene sets. NES, normalized enrichment score. ( E ) mRNA expression levels of inflammation related genes were analyzed by qRT‒PCR and normalized to β-actin. Data are presented as the mean ± S.D. (*p < 0.05; **p < 0.01)

To confirm the RNA-seq results, we assessed the expression levels of the proinflammatory genes NLRP3 , IL-1β , IL-6 , IL-8 , and TNF-α by qRT-PCR. 3R4F treatment increased the expression of these proinflammatory genes in hMSCs. Similarly, we identified that IL-10 and IDO , known immune suppressive factors of MSCs, were both downregulated by 3R4F treatment (Fig.  2 E). Additionally, 3R4F inhibited the anti-proliferative effect of hMSCs on T lymphocytes (Additional file 1: Fig. S4 A). Collectively, 3R4F perturbs immune homeostasis by altering global gene expression patterns of hMSCs, with functional consequences demonstrated in vitro.

3R4F-induced ROS reduce the hematopoietic supportive function of hMSCs

It has been reported that accumulated ROS inhibit the HSPC-supporting ability of stromal cells in aged mice [ 25 ]. In a similar context, our RNA-seq results indicated that 3R4F-treated hMSCs developed a gene expression GO profile suggesting excess ROS (Fig.  2 C, D). We measured the mRNA expression level of ROS-related genes including AhR, CYP1A1 , and NOS2 . All were upregulated in hMSCs following 3R4F exposure (Fig.  3 A). We also verified that exposure led to the induction of intracellular ROS by the DCFDA assay. 3R4F-treated hMSCs showed increased intracellular ROS levels, which were reduced by pretreatment with N-acetyl cysteine (NAC; ROS inhibitor) (Fig.  3 B). A recent study showed that oxidative stress by ROS inhibits the metabolic activity of hMSCs [ 26 ]. We performed real-time metabolic analysis to measure the basal respiration of hMSCs with 5% 3R4F exposure, showing significantly reduced basal oxygen consumption rate (OCR). Pretreatment with NAC attenuated the reduced OCR of the 3R4F-treated hMSCs (Fig.  3 C).

3R4F-exposure induces ROS in hMSCs, resulting in a reduction in the supporting ability of HSPCs. ( A ) mRNA expression levels of ROS-related genes ( AhR , CYP1A1 , and NOS2 ) in 3R4F-treated hMSCs were analyzed by qRT‒PCR. The expression level of each gene was normalized to that of β-actin. ( B-D ) hMSCs were pretreated with or without NAC for 1 h and followed by treatment with 5% 3R4F for 72 h. ( B ) Intracellular ROS levels were measured by flow cytometric analysis by using the ROS-sensitive fluorophore 2’,7’-dichlorofluorescin diacetate (DCFDA). ( C ) The basal level of the cellular respiration rate (oxygen consumption rate [OCR]) was determined by using an XFe24 Extracellular Flux Analyzer. ( D ) mRNA expression level of HSPC niche related genes in 3R4F-treated MSCs were analyzed by qRT-PCR and normalized to that of β-actin. ( E-G ) hCD34 + HSPCs were cocultured with 3R4F-treated hMSCs with or without NAC pretreatment for 72 h. ( E ) After 3 days of coculture, the CD34 + CD90 + HSPC population in CD45 + cells were analyzed using flow cytometry. ( F, G ) After coculture, HSPCs were seeded in methylcellulose colony formation medium and cultured for 2 weeks. ( F ) Representative colony morphologies (Scale bar: 200 μm). ( G ) The number of BFU-E, CFU-GM, CFU-GEMM, and the total sum of all colonies were quantified. ( H ) hMSCs were pretreated with or without NAC for 1 h and followed by treatment with 5% 3R4F for 48 h. mRNA expression levels of inflammation-related genes ( IL-6 , IL-8 , TNF-α , cFOS , and IL-10 ) were determined by qRT-PCR. The expression level of each gene was normalized to that of β-actin. The data are presented as the mean ± S.D. of three independent experiments (*p < 0.05; **p < 0.01). BFU-E – Burst forming Erythrocyte; GM – Granulocyte/Macrophage; GEMM – Granulocyte/Erythrocyte/Macrophage/Megakaryocyte.

In vitro coculture of human HSPCs on MSCs can preserve or augment their viability, self-renewal and engraftment capabilities [ 27 , 28 ]. To assess the impact of CSE on this supportive function of hMSCs on HSPCs, we assessed the mRNA expression levels of the niche-related genes SCF, CXCL12 , and VCAM1 in hMSCs. Their expression was suppressed by exposure to 3R4F and recovered by the introduction of a ROS inhibitor (Fig.  3 D). Next, human CD34 + HPSCs were cocultured with hMSCs with or without 3R4F exposure to investigate the effect of CSE on the supportive role of MSCs in maintaining the more primitive fraction of CD34 + CD90 + cells as quantified by flow cytometric analysis. The proportion of CD34 + CD90 + HSPCs was improved by the presence of hMSCs, and this supportive ability was decreased by 3R4F pretreatment of the hMSCs, while ROS inhibition by NAC during hMSC exposure to 3R4F rescued the supportive effect of the hMSCs on CD34 + CD90 + cells (Fig.  3 E and Additional file 1: Fig. S4 B). Plating of hematopoietic colonies (CFU) following coculture of CD34 + HSPC on hMSCs pre-treated with 3R4F showed a reduction in myeloid lineage colonies (CFU-GM and CFU-GEMM), again rescued by ROS inhibition during hMSC 3R4F pre-treatment. There was no significant change in the number of erythroid colonies (Fig.  3 F, G and Additional file 1: Fig. S4 C). Given that a proinflammatory milieu has been reported to disrupt HSPC-supporting properties of hMSCs [ 29 ], we measured inflammation-related gene expression in 3R4F-treated hMSCs. Proinflammatory genes, including IL-6, IL-8, TNF-α , and cFOS , were increased, whereas IL-10 , an anti-inflammatory gene, was reduced. Pretreatment with NAC protected against these changes in gene expression (Fig.  3 H).

NAC ameliorates the 3R4F-induced dysfunction of the HSPC-supporting ability of hMSCs

We next studied the impact of CSE on the ability of hMSCs to support the engraftment potential of hHSPCs. Human CD34 + HSPCs were cocultured for 3 days with control or 3R4F-treated hMSCs, with or without NAC, and administered to NSG mice (Fig.  4 A). Blood was collected 8 weeks after transplantation and analyzed by flow cytometry for hCD45 to measure human HSPC engraftment. Coculture with 3R4F-treated hMSCs markedly decreased the engraftment capacity of HSPCs compared to coculture with control hMSCs. Moreover, this reduction was attenuated by pretreatment with NAC (Fig.  4 B). At 15 weeks post transplantation, BM and PB samples were harvested and the fraction of hCD45 + cells was analyzed. Similar to the 8 weeks PB analysis, both BM and PB from 15 weeks showed a significantly reduced hCD45 + proportion for mice receiving HSPCs cultured with 3R4F treated hMSC that was restored by ROS inhibition (Fig.  4 B). Lineage analysis within the human CD45 + compartment showed no difference in HSPC production of myeloid, T cell and B cell lineages when exposed to 3R4F-treated hMSCs compared to control hMSCs (Fig.  4 C). Collectively, these results suggest that 3R4F-induced ROS disrupt the niche function of hMSCs in the engraftment capacity of HSPCs during in vitro culture, while ROS inhibition effectively restores the decreased engraftment.

ROS inhibition restores the impaired HSPC supporting ability of hMSCs and engraftment in xenotransplantation model. ( A ) A schematic diagram of ROS inhibition in hMSCs and following hMSC-cocultured HSPC transplantation. hMSCs were pretreated with or without NAC for 1 h, and followed by treatment with 5% 3R4F for 72 h. CD34 + HSPC were cocultured with 3R4F-treated hMSC. After 3 days, cocultured HSPCs were harvested, enriched via magnetic sorting, and intravenously injected into NSG mice. PB and BM samples were collected at the indicated timepoints for further analyses. ( B ) HSPC engraftment was evaluated by determining hCD45 + cells from PB 8 weeks post transplantation. ( C ) Repopulation of blood lineage cells (hCD3 + T cells, hCD14 + monocytes, hCD20 + B cells, hCD33 + myeloid cells) was analyzed in the PB and BM of NSG mice at 15 weeks post transplantation. n = 3–4 mice/group. The data are presented as the mean ± S.D. of three independent experiments (*p < 0.05; **p < 0.01)

3R4F-induced ROS regulates the hematopoietic supportive function via NLRP3 in hMSCs

Given the above results, we hypothesized that CSE impacted the ability of hMSCs to support HSPCs via activation of the NLRP3 inflammasome. We observed that ROS and NLRP3 were positively regulated by each other in the analysis of the DEG profile using IPA (Fig.  5 A). qRT-PCR analysis confirmed that ROS scavenging by NAC reduced the expression of NLRP3 inflammasome-related genes in 3R4F-treated hMSCs (Fig.  5 B). We examined the impact of adding MCC950, an NLRP3 inhibitor, during hMSC 3R4F pre-treatment, and assessed its effects on HSPC-supporting abilities. We confirmed that the 3R4F-induced NLRP3 inflammasome pathway was partially blocked by MCC950, with decreases in the expression of NLRP3, IL-1β , and CASP1 (Fig.  5 C). Consistent with the mRNA expression results, the NLRP3 inflammasome-related proteins (NLRP3, ASC, CASP1, and IL-1β) expression levels were induced in hMSCs by the 3R4F treatment, while pretreatment with NAC and MCC950 efficiently prevented the effect of 3R4F (Fig. 5 D). Pretreatment with MCC950 indeed ameliorated the impact of 3R4F exposure on hMSCs in supporting CD34 + CD90 + HSPCs (Fig.  5 E), and on the number of CFU-GM and CFU-GEMM colonies (Fig.  5 F and Additional file 1: Fig. S5 A). Thus, inhibition of NLRP3 restores the HSPC-supporting ability of CSE-treated hMSCs.

3R4F-induced ROS impair hematopoiesis supportive ability of hMSCs via the NLRP3 inflammasome. ( A ) An illustration of 3R4F-induced ROS activation and the NLRP3 expression-related pathway was depicted based on the DEG profile of hMSCs. IPA software was used for in silico analysis. ( B, C, D ) hMSCs were pretreated with or without NAC or MCC950 for 1 h and followed by treatment with 5% 3R4F for 72 h. ( B ) The mRNA expression levels of NLRP3 inflammasome related genes ( NLRP3 , PYCARD , and IL-1β ) was analyzed by qRT‒PCR. The expression level of each gene was normalized to that of β-actin. ( C ) mRNA expression level of inflammation related genes ( NLRP3 , CASP1, IL-1β , and IL-10 ) were analyzed by qRT‒PCR. The expression level of each gene was normalized to that of β-actin. ( D ) The expression of NLRP3, ASC, pro/cleaved Caspase-1, and pro/cleaved IL-1β was analyzed and quantified by western blotting. ( E ) MCC950-treated hMSCs were cocultured with hCD34 + HSPCs for 3days. CD34 + CD90 + HSPC population in CD45 + cells was analyzed using flow cytometry. ( F ) Three days after coculture, HSPCs were seeded in methylcellulose colony formation medium and cultured for 2 weeks. The number of BFU-E, CFU-GM, CFU-GEMM, and the total sum of all colonies were quantified. Data are presented as the mean ± S.D. (*p < 0.05; **p < 0.01; ***p < 0.001). BFU-E – Burst forming Erythrocyte; GM – Granulocyte/Macrophage; GEMM – Granulocyte/Erythrocyte/Macrophage/Megakaryocyte.

Although it has been observed that smokers tend to exhibit reduced posttransplant survival rates and increased mortality following allogeneic HSPC transplantation [ 30 , 31 , 32 , 33 ], the potential role of impaired hematopoietic niche function has not been explored in depth. We conducted a comprehensive analysis of the influence of CSE on MSC characteristics and MSC-HSPC interactions. The reference compound we utilized, 3R4F, contains 9.4 mg of tar and 0.73 mg of nicotine per cigarette [ 34 , 35 ] and is commonly used for toxicity assessments, such ROS production, inflammation, and cellular damage to a range of cells, including bronchial epithelial cells and vascular endothelial cells [ 35 , 36 , 37 ]. Past studies have suggested that CS impairs the characteristics of BM-MSCs in the bone marrow environment. However, these studies have primarily focused on phenotypic changes in the bone marrow microenvironment, such as reductions in HSPC pool size or decreased proliferative capacity of BM-MSCs [ 11 , 38 ].

CSE-induced excessive production of ROS and resultant oxidative stress are widely recognized as key contributors to the development of diverse physiological impairments and disorders. We carried out an in-depth investigation of the impact of CSE on BM niche function, both in vivo via exposure of mice to 3R4F prior to transplantation of HSPCs, and ex vivo via exposure of hMSCs to 3R4F prior to coculture with HSPCs. Pre-treatment of mice resulted in impaired engraftment of HSPCs, potentially due to impact on the BM niche. Meanwhile, we analyzed the transcriptomic profile of CSE-exposed hMSCs to elucidate the underlying mechanisms and revealed the activation of pathways related to tissue damage, inflammation, and aging, consistent with previously documented effects. Notably, an increase in the production of ROS was observed. Through in silico and functional analyses, we explored the potential mechanisms through which elevated ROS levels may compromise the HSPC-supportive role of MSCs. The remarkable decrease in HSPC engraftment efficiency resulting from exposure to 3R4F in the NSG mice model implies that these effects might be further exacerbated within a biological system, notably in humans. Furthermore, we provide evidence that inhibition of ROS restores CSE-mediated HSPC-supporting ability of hMSCs, suggesting that CSE-induced ROS may play a key role in the interaction between BM niche stem cells and HSPC engraftment.

Previous studies have shown that the NLRP3 inflammasome is involved in the development of hematologic diseases and plays a role in regulating hematopoiesis. S100A9 activates the ROS-dependent NLRP3 inflammasome and induces pyroptotic cell death and clonal expansion of HSPCs in myelodysplastic syndrome (MDS) patients [ 39 , 40 ]. However, there is limited information regarding the relationship between ROS-induced activation of the NLRP3 inflammasome and MSCs within the hematopoietic niche. Our studies demonstrated that the NLRP3 inflammasome was activated, followed by ROS induction, and the suppression of ROS or NLRP3 activation possibly restored the impaired HSPC-supporting ability of MSCs. This study thus demonstrates that the activation of ROS/NLRP3 inflammasome serves as a causative factor in impaired HSC engraftment postsmoking exposure, potentially impeding the natural hematopoietic supportive function of hMSCs.

It is suggested that stem cell properties derived from different sources may be distinct depending on their tissue of origin. Consequently, tailoring the utilization of MSCs or MSC-derived extracellular vesicles (EVs) based on their sources and specialized function is recommended [ 41 , 42 , 43 ]. Therefore, subsequent research will potentially envision more specific phenotyping and mechanistic studies of MSCs from different origins focusing on their direct HSPC-supporting capacity. Nevertheless, it is noteworthy that the direct assessment of the impact of human MSCs in an in vivo setting, achieved by transplanting human HSPCs cocultured with human MSCs to NSG mice, carries scientific and preclinical significance.

In light of these considerations, it is evident that in future endeavors involving HSPC transplantation or cell-based therapeutic approaches, the influence of smoking when employing MSCs should be underscored and carefully considered. Consequently, this study systematically analyzed the effects that smoking can have on transplanted HSPCs and hematopoietic niche and, furthermore, has provided clinical significance by emphasizing the need for the selective application of MSCs as adjuncts in HSPC transplantation [ 8 , 44 , 45 ].

Conclusions

In conclusion, our study elucidates that activation of the ROS/NLRP3 pathway disrupts the hematopoietic support function of hMSCs following CSE treatment, thereby impairing HSPC engraftment. We found that tissue damage, inflammation, and aging-related genes were significantly upregulated upon CSE exposure. Notably, inhibition of CSE-induced ROS/NLRP3 pathway was effective in restoring the HSPCs supportive function of CSE-treated hMSCs. Taken together, our research provides valuable insights into the niche signals that influence hematopoietic system regulation in the bone marrow. This, in turn, contributes potential strategies to mitigate the adverse effects of smoking on stem cell therapies.

Data availability

All data are included in the text and supplementary materials. Data details are available from the corresponding author on request.

Abbreviations

Mesenchymal stem cell

• Cigarette smoking extract

Bone marrow

Hematopoietic stem and progenitor cells

• Reactive oxygen species

oxygen consumption rate

Colony forming unit

N-acetyl-l-cysteine

Nucleotide-binding domain-like receptor protein-3

Umbilical cord blood

Mononuclear cells

Differentially expressed genes

Gene ontology biological process

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Acknowledgements

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This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development institution (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-00265442).

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Hyun Sung Park and Byung-Chul Lee contributed equally to this work.

Authors and Affiliations

Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea

Hyun Sung Park, Dong-Hoon Chae, Aaron Yu, Jae Han Park, Jiyoung Heo, Myoung Hee Han, Keonwoo Cho, Mi-Kyung Oh & Kyung-Rok Yu

Department of Biological Sciences, Sookmyung Women’s University, Seoul, Korea

Byung-Chul Lee

Research Institute of Women’s Health, Sookmyung Women’s University, Seoul, Korea

Division of Allergy and Respiratory Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Korea

Joong Won Lee & Ji-Won Jung

Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD, USA

Cynthia E. Dunbar

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Conceptualization, H.S.P., B.-C.L., M.-K.O., and K.-R.Y.; Methodology, H.S.P., B.-C.L., D.-H.C., J.W.L., J.W.J., and C.E.D.; Investigation, H.S.P., B.-C.L., D.-H.C., A.Y., J.H.P., J.Y.H., M.H.H., and K.C.; Writing, H.S.P., B.-C.L., M.-K.O., and K.-R.Y.; Funding Acquisition, K.-R.Y.; Supervision, M.-K.O., and K.-R.Y. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Mi-Kyung Oh or Kyung-Rok Yu .

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All umbilical cord blood (UCB) units were obtained from the Seoul Metropolitan Government Public Cord Blood Bank (ALLCORD) under approval of the Institutional Review Board (IRB) of the Seoul National University (IRB No. E2212/004 − 001, “Establishing humanized mouse model using UCB derived Hematopoietic stem cell”, November 11, 2023). All animal experiments were conducted in accordance with the ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) and approved by the Institutional Animal Care and Use Committee of Seoul National University (SNU-201120-1-4, “Study on the effect of cigarette smoke extract (CSE) on hematopoietic stem cell (HSC) transplantation in humanized mouse model” approved on August 09, 2023).

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Park, H., Lee, BC., Chae, DH. et al. Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation. Stem Cell Res Ther 15 , 145 (2024). https://doi.org/10.1186/s13287-024-03731-2

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Cultural Relativity and Acceptance of Embryonic Stem Cell Research

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Main Article Content

There is a debate about the ethical implications of using human embryos in stem cell research, which can be influenced by cultural, moral, and social values. This paper argues for an adaptable framework to accommodate diverse cultural and religious perspectives. By using an adaptive ethics model, research protections can reflect various populations and foster growth in stem cell research possibilities.

INTRODUCTION

Stem cell research combines biology, medicine, and technology, promising to alter health care and the understanding of human development. Yet, ethical contention exists because of individuals’ perceptions of using human embryos based on their various cultural, moral, and social values. While these disagreements concerning policy, use, and general acceptance have prompted the development of an international ethics policy, such a uniform approach can overlook the nuanced ethical landscapes between cultures. With diverse viewpoints in public health, a single global policy, especially one reflecting Western ethics or the ethics prevalent in high-income countries, is impractical. This paper argues for a culturally sensitive, adaptable framework for the use of embryonic stem cells. Stem cell policy should accommodate varying ethical viewpoints and promote an effective global dialogue. With an extension of an ethics model that can adapt to various cultures, we recommend localized guidelines that reflect the moral views of the people those guidelines serve.

Stem cells, characterized by their unique ability to differentiate into various cell types, enable the repair or replacement of damaged tissues. Two primary types of stem cells are somatic stem cells (adult stem cells) and embryonic stem cells. Adult stem cells exist in developed tissues and maintain the body’s repair processes. [1] Embryonic stem cells (ESC) are remarkably pluripotent or versatile, making them valuable in research. [2] However, the use of ESCs has sparked ethics debates. Considering the potential of embryonic stem cells, research guidelines are essential. The International Society for Stem Cell Research (ISSCR) provides international stem cell research guidelines. They call for “public conversations touching on the scientific significance as well as the societal and ethical issues raised by ESC research.” [3] The ISSCR also publishes updates about culturing human embryos 14 days post fertilization, suggesting local policies and regulations should continue to evolve as ESC research develops. [4]  Like the ISSCR, which calls for local law and policy to adapt to developing stem cell research given cultural acceptance, this paper highlights the importance of local social factors such as religion and culture.

I.     Global Cultural Perspective of Embryonic Stem Cells

Views on ESCs vary throughout the world. Some countries readily embrace stem cell research and therapies, while others have stricter regulations due to ethical concerns surrounding embryonic stem cells and when an embryo becomes entitled to moral consideration. The philosophical issue of when the “someone” begins to be a human after fertilization, in the morally relevant sense, [5] impacts when an embryo becomes not just worthy of protection but morally entitled to it. The process of creating embryonic stem cell lines involves the destruction of the embryos for research. [6] Consequently, global engagement in ESC research depends on social-cultural acceptability.

a.     US and Rights-Based Cultures

In the United States, attitudes toward stem cell therapies are diverse. The ethics and social approaches, which value individualism, [7] trigger debates regarding the destruction of human embryos, creating a complex regulatory environment. For example, the 1996 Dickey-Wicker Amendment prohibited federal funding for the creation of embryos for research and the destruction of embryos for “more than allowed for research on fetuses in utero.” [8] Following suit, in 2001, the Bush Administration heavily restricted stem cell lines for research. However, the Stem Cell Research Enhancement Act of 2005 was proposed to help develop ESC research but was ultimately vetoed. [9] Under the Obama administration, in 2009, an executive order lifted restrictions allowing for more development in this field. [10] The flux of research capacity and funding parallels the different cultural perceptions of human dignity of the embryo and how it is socially presented within the country’s research culture. [11]

b.     Ubuntu and Collective Cultures

African bioethics differs from Western individualism because of the different traditions and values. African traditions, as described by individuals from South Africa and supported by some studies in other African countries, including Ghana and Kenya, follow the African moral philosophies of Ubuntu or Botho and Ukama , which “advocates for a form of wholeness that comes through one’s relationship and connectedness with other people in the society,” [12] making autonomy a socially collective concept. In this context, for the community to act autonomously, individuals would come together to decide what is best for the collective. Thus, stem cell research would require examining the value of the research to society as a whole and the use of the embryos as a collective societal resource. If society views the source as part of the collective whole, and opposes using stem cells, compromising the cultural values to pursue research may cause social detachment and stunt research growth. [13] Based on local culture and moral philosophy, the permissibility of stem cell research depends on how embryo, stem cell, and cell line therapies relate to the community as a whole . Ubuntu is the expression of humanness, with the person’s identity drawn from the “’I am because we are’” value. [14] The decision in a collectivistic culture becomes one born of cultural context, and individual decisions give deference to others in the society.

Consent differs in cultures where thought and moral philosophy are based on a collective paradigm. So, applying Western bioethical concepts is unrealistic. For one, Africa is a diverse continent with many countries with different belief systems, access to health care, and reliance on traditional or Western medicines. Where traditional medicine is the primary treatment, the “’restrictive focus on biomedically-related bioethics’” [is] problematic in African contexts because it neglects bioethical issues raised by traditional systems.” [15] No single approach applies in all areas or contexts. Rather than evaluating the permissibility of ESC research according to Western concepts such as the four principles approach, different ethics approaches should prevail.

Another consideration is the socio-economic standing of countries. In parts of South Africa, researchers have not focused heavily on contributing to the stem cell discourse, either because it is not considered health care or a health science priority or because resources are unavailable. [16] Each country’s priorities differ given different social, political, and economic factors. In South Africa, for instance, areas such as maternal mortality, non-communicable diseases, telemedicine, and the strength of health systems need improvement and require more focus. [17] Stem cell research could benefit the population, but it also could divert resources from basic medical care. Researchers in South Africa adhere to the National Health Act and Medicines Control Act in South Africa and international guidelines; however, the Act is not strictly enforced, and there is no clear legislation for research conduct or ethical guidelines. [18]

Some parts of Africa condemn stem cell research. For example, 98.2 percent of the Tunisian population is Muslim. [19] Tunisia does not permit stem cell research because of moral conflict with a Fatwa. Religion heavily saturates the regulation and direction of research. [20] Stem cell use became permissible for reproductive purposes only recently, with tight restrictions preventing cells from being used in any research other than procedures concerning ART/IVF.  Their use is conditioned on consent, and available only to married couples. [21] The community's receptiveness to stem cell research depends on including communitarian African ethics.

c.     Asia

Some Asian countries also have a collective model of ethics and decision making. [22] In China, the ethics model promotes a sincere respect for life or human dignity, [23] based on protective medicine. This model, influenced by Traditional Chinese Medicine (TCM), [24] recognizes Qi as the vital energy delivered via the meridians of the body; it connects illness to body systems, the body’s entire constitution, and the universe for a holistic bond of nature, health, and quality of life. [25] Following a protective ethics model, and traditional customs of wholeness, investment in stem cell research is heavily desired for its applications in regenerative therapies, disease modeling, and protective medicines. In a survey of medical students and healthcare practitioners, 30.8 percent considered stem cell research morally unacceptable while 63.5 percent accepted medical research using human embryonic stem cells. Of these individuals, 89.9 percent supported increased funding for stem cell research. [26] The scientific community might not reflect the overall population. From 1997 to 2019, China spent a total of $576 million (USD) on stem cell research at 8,050 stem cell programs, increased published presence from 0.6 percent to 14.01 percent of total global stem cell publications as of 2014, and made significant strides in cell-based therapies for various medical conditions. [27] However, while China has made substantial investments in stem cell research and achieved notable progress in clinical applications, concerns linger regarding ethical oversight and transparency. [28] For example, the China Biosecurity Law, promoted by the National Health Commission and China Hospital Association, attempted to mitigate risks by introducing an institutional review board (IRB) in the regulatory bodies. 5800 IRBs registered with the Chinese Clinical Trial Registry since 2021. [29] However, issues still need to be addressed in implementing effective IRB review and approval procedures.

The substantial government funding and focus on scientific advancement have sometimes overshadowed considerations of regional cultures, ethnic minorities, and individual perspectives, particularly evident during the one-child policy era. As government policy adapts to promote public stability, such as the change from the one-child to the two-child policy, [30] research ethics should also adapt to ensure respect for the values of its represented peoples.

Japan is also relatively supportive of stem cell research and therapies. Japan has a more transparent regulatory framework, allowing for faster approval of regenerative medicine products, which has led to several advanced clinical trials and therapies. [31] South Korea is also actively engaged in stem cell research and has a history of breakthroughs in cloning and embryonic stem cells. [32] However, the field is controversial, and there are issues of scientific integrity. For example, the Korean FDA fast-tracked products for approval, [33] and in another instance, the oocyte source was unclear and possibly violated ethical standards. [34] Trust is important in research, as it builds collaborative foundations between colleagues, trial participant comfort, open-mindedness for complicated and sensitive discussions, and supports regulatory procedures for stakeholders. There is a need to respect the culture’s interest, engagement, and for research and clinical trials to be transparent and have ethical oversight to promote global research discourse and trust.

d.     Middle East

Countries in the Middle East have varying degrees of acceptance of or restrictions to policies related to using embryonic stem cells due to cultural and religious influences. Saudi Arabia has made significant contributions to stem cell research, and conducts research based on international guidelines for ethical conduct and under strict adherence to guidelines in accordance with Islamic principles. Specifically, the Saudi government and people require ESC research to adhere to Sharia law. In addition to umbilical and placental stem cells, [35] Saudi Arabia permits the use of embryonic stem cells as long as they come from miscarriages, therapeutic abortions permissible by Sharia law, or are left over from in vitro fertilization and donated to research. [36] Laws and ethical guidelines for stem cell research allow the development of research institutions such as the King Abdullah International Medical Research Center, which has a cord blood bank and a stem cell registry with nearly 10,000 donors. [37] Such volume and acceptance are due to the ethical ‘permissibility’ of the donor sources, which do not conflict with religious pillars. However, some researchers err on the side of caution, choosing not to use embryos or fetal tissue as they feel it is unethical to do so. [38]

Jordan has a positive research ethics culture. [39] However, there is a significant issue of lack of trust in researchers, with 45.23 percent (38.66 percent agreeing and 6.57 percent strongly agreeing) of Jordanians holding a low level of trust in researchers, compared to 81.34 percent of Jordanians agreeing that they feel safe to participate in a research trial. [40] Safety testifies to the feeling of confidence that adequate measures are in place to protect participants from harm, whereas trust in researchers could represent the confidence in researchers to act in the participants’ best interests, adhere to ethical guidelines, provide accurate information, and respect participants’ rights and dignity. One method to improve trust would be to address communication issues relevant to ESC. Legislation surrounding stem cell research has adopted specific language, especially concerning clarification “between ‘stem cells’ and ‘embryonic stem cells’” in translation. [41] Furthermore, legislation “mandates the creation of a national committee… laying out specific regulations for stem-cell banking in accordance with international standards.” [42] This broad regulation opens the door for future global engagement and maintains transparency. However, these regulations may also constrain the influence of research direction, pace, and accessibility of research outcomes.

e.     Europe

In the European Union (EU), ethics is also principle-based, but the principles of autonomy, dignity, integrity, and vulnerability are interconnected. [43] As such, the opportunity for cohesion and concessions between individuals’ thoughts and ideals allows for a more adaptable ethics model due to the flexible principles that relate to the human experience The EU has put forth a framework in its Convention for the Protection of Human Rights and Dignity of the Human Being allowing member states to take different approaches. Each European state applies these principles to its specific conventions, leading to or reflecting different acceptance levels of stem cell research. [44]

For example, in Germany, Lebenzusammenhang , or the coherence of life, references integrity in the unity of human culture. Namely, the personal sphere “should not be subject to external intervention.” [45]  Stem cell interventions could affect this concept of bodily completeness, leading to heavy restrictions. Under the Grundgesetz, human dignity and the right to life with physical integrity are paramount. [46] The Embryo Protection Act of 1991 made producing cell lines illegal. Cell lines can be imported if approved by the Central Ethics Commission for Stem Cell Research only if they were derived before May 2007. [47] Stem cell research respects the integrity of life for the embryo with heavy specifications and intense oversight. This is vastly different in Finland, where the regulatory bodies find research more permissible in IVF excess, but only up to 14 days after fertilization. [48] Spain’s approach differs still, with a comprehensive regulatory framework. [49] Thus, research regulation can be culture-specific due to variations in applied principles. Diverse cultures call for various approaches to ethical permissibility. [50] Only an adaptive-deliberative model can address the cultural constructions of self and achieve positive, culturally sensitive stem cell research practices. [51]

II.     Religious Perspectives on ESC

Embryonic stem cell sources are the main consideration within religious contexts. While individuals may not regard their own religious texts as authoritative or factual, religion can shape their foundations or perspectives.

The Qur'an states:

“And indeed We created man from a quintessence of clay. Then We placed within him a small quantity of nutfa (sperm to fertilize) in a safe place. Then We have fashioned the nutfa into an ‘alaqa (clinging clot or cell cluster), then We developed the ‘alaqa into mudgha (a lump of flesh), and We made mudgha into bones, and clothed the bones with flesh, then We brought it into being as a new creation. So Blessed is Allah, the Best of Creators.” [52]

Many scholars of Islam estimate the time of soul installment, marked by the angel breathing in the soul to bring the individual into creation, as 120 days from conception. [53] Personhood begins at this point, and the value of life would prohibit research or experimentation that could harm the individual. If the fetus is more than 120 days old, the time ensoulment is interpreted to occur according to Islamic law, abortion is no longer permissible. [54] There are a few opposing opinions about early embryos in Islamic traditions. According to some Islamic theologians, there is no ensoulment of the early embryo, which is the source of stem cells for ESC research. [55]

In Buddhism, the stance on stem cell research is not settled. The main tenets, the prohibition against harming or destroying others (ahimsa) and the pursuit of knowledge (prajña) and compassion (karuna), leave Buddhist scholars and communities divided. [56] Some scholars argue stem cell research is in accordance with the Buddhist tenet of seeking knowledge and ending human suffering. Others feel it violates the principle of not harming others. Finding the balance between these two points relies on the karmic burden of Buddhist morality. In trying to prevent ahimsa towards the embryo, Buddhist scholars suggest that to comply with Buddhist tenets, research cannot be done as the embryo has personhood at the moment of conception and would reincarnate immediately, harming the individual's ability to build their karmic burden. [57] On the other hand, the Bodhisattvas, those considered to be on the path to enlightenment or Nirvana, have given organs and flesh to others to help alleviate grieving and to benefit all. [58] Acceptance varies on applied beliefs and interpretations.

Catholicism does not support embryonic stem cell research, as it entails creation or destruction of human embryos. This destruction conflicts with the belief in the sanctity of life. For example, in the Old Testament, Genesis describes humanity as being created in God’s image and multiplying on the Earth, referencing the sacred rights to human conception and the purpose of development and life. In the Ten Commandments, the tenet that one should not kill has numerous interpretations where killing could mean murder or shedding of the sanctity of life, demonstrating the high value of human personhood. In other books, the theological conception of when life begins is interpreted as in utero, [59] highlighting the inviolability of life and its formation in vivo to make a religious point for accepting such research as relatively limited, if at all. [60] The Vatican has released ethical directives to help apply a theological basis to modern-day conflicts. The Magisterium of the Church states that “unless there is a moral certainty of not causing harm,” experimentation on fetuses, fertilized cells, stem cells, or embryos constitutes a crime. [61] Such procedures would not respect the human person who exists at these stages, according to Catholicism. Damages to the embryo are considered gravely immoral and illicit. [62] Although the Catholic Church officially opposes abortion, surveys demonstrate that many Catholic people hold pro-choice views, whether due to the context of conception, stage of pregnancy, threat to the mother’s life, or for other reasons, demonstrating that practicing members can also accept some but not all tenets. [63]

Some major Jewish denominations, such as the Reform, Conservative, and Reconstructionist movements, are open to supporting ESC use or research as long as it is for saving a life. [64] Within Judaism, the Talmud, or study, gives personhood to the child at birth and emphasizes that life does not begin at conception: [65]

“If she is found pregnant, until the fortieth day it is mere fluid,” [66]

Whereas most religions prioritize the status of human embryos, the Halakah (Jewish religious law) states that to save one life, most other religious laws can be ignored because it is in pursuit of preservation. [67] Stem cell research is accepted due to application of these religious laws.

We recognize that all religions contain subsets and sects. The variety of environmental and cultural differences within religious groups requires further analysis to respect the flexibility of religious thoughts and practices. We make no presumptions that all cultures require notions of autonomy or morality as under the common morality theory , which asserts a set of universal moral norms that all individuals share provides moral reasoning and guides ethical decisions. [68] We only wish to show that the interaction with morality varies between cultures and countries.

III.     A Flexible Ethical Approach

The plurality of different moral approaches described above demonstrates that there can be no universally acceptable uniform law for ESC on a global scale. Instead of developing one standard, flexible ethical applications must be continued. We recommend local guidelines that incorporate important cultural and ethical priorities.

While the Declaration of Helsinki is more relevant to people in clinical trials receiving ESC products, in keeping with the tradition of protections for research subjects, consent of the donor is an ethical requirement for ESC donation in many jurisdictions including the US, Canada, and Europe. [69] The Declaration of Helsinki provides a reference point for regulatory standards and could potentially be used as a universal baseline for obtaining consent prior to gamete or embryo donation.

For instance, in Columbia University’s egg donor program for stem cell research, donors followed standard screening protocols and “underwent counseling sessions that included information as to the purpose of oocyte donation for research, what the oocytes would be used for, the risks and benefits of donation, and process of oocyte stimulation” to ensure transparency for consent. [70] The program helped advance stem cell research and provided clear and safe research methods with paid participants. Though paid participation or covering costs of incidental expenses may not be socially acceptable in every culture or context, [71] and creating embryos for ESC research is illegal in many jurisdictions, Columbia’s program was effective because of the clear and honest communications with donors, IRBs, and related stakeholders.  This example demonstrates that cultural acceptance of scientific research and of the idea that an egg or embryo does not have personhood is likely behind societal acceptance of donating eggs for ESC research. As noted, many countries do not permit the creation of embryos for research.

Proper communication and education regarding the process and purpose of stem cell research may bolster comprehension and garner more acceptance. “Given the sensitive subject material, a complete consent process can support voluntary participation through trust, understanding, and ethical norms from the cultures and morals participants value. This can be hard for researchers entering countries of different socioeconomic stability, with different languages and different societal values. [72]

An adequate moral foundation in medical ethics is derived from the cultural and religious basis that informs knowledge and actions. [73] Understanding local cultural and religious values and their impact on research could help researchers develop humility and promote inclusion.

IV.     Concerns

Some may argue that if researchers all adhere to one ethics standard, protection will be satisfied across all borders, and the global public will trust researchers. However, defining what needs to be protected and how to define such research standards is very specific to the people to which standards are applied. We suggest that applying one uniform guide cannot accurately protect each individual because we all possess our own perceptions and interpretations of social values. [74] Therefore, the issue of not adjusting to the moral pluralism between peoples in applying one standard of ethics can be resolved by building out ethics models that can be adapted to different cultures and religions.

Other concerns include medical tourism, which may promote health inequities. [75] Some countries may develop and approve products derived from ESC research before others, compromising research ethics or drug approval processes. There are also concerns about the sale of unauthorized stem cell treatments, for example, those without FDA approval in the United States. Countries with robust research infrastructures may be tempted to attract medical tourists, and some customers will have false hopes based on aggressive publicity of unproven treatments. [76]

For example, in China, stem cell clinics can market to foreign clients who are not protected under the regulatory regimes. Companies employ a marketing strategy of “ethically friendly” therapies. Specifically, in the case of Beike, China’s leading stem cell tourism company and sprouting network, ethical oversight of administrators or health bureaus at one site has “the unintended consequence of shifting questionable activities to another node in Beike's diffuse network.” [77] In contrast, Jordan is aware of stem cell research’s potential abuse and its own status as a “health-care hub.” Jordan’s expanded regulations include preserving the interests of individuals in clinical trials and banning private companies from ESC research to preserve transparency and the integrity of research practices. [78]

The social priorities of the community are also a concern. The ISSCR explicitly states that guidelines “should be periodically revised to accommodate scientific advances, new challenges, and evolving social priorities.” [79] The adaptable ethics model extends this consideration further by addressing whether research is warranted given the varying degrees of socioeconomic conditions, political stability, and healthcare accessibilities and limitations. An ethical approach would require discussion about resource allocation and appropriate distribution of funds. [80]

While some religions emphasize the sanctity of life from conception, which may lead to public opposition to ESC research, others encourage ESC research due to its potential for healing and alleviating human pain. Many countries have special regulations that balance local views on embryonic personhood, the benefits of research as individual or societal goods, and the protection of human research subjects. To foster understanding and constructive dialogue, global policy frameworks should prioritize the protection of universal human rights, transparency, and informed consent. In addition to these foundational global policies, we recommend tailoring local guidelines to reflect the diverse cultural and religious perspectives of the populations they govern. Ethics models should be adapted to local populations to effectively establish research protections, growth, and possibilities of stem cell research.

For example, in countries with strong beliefs in the moral sanctity of embryos or heavy religious restrictions, an adaptive model can allow for discussion instead of immediate rejection. In countries with limited individual rights and voice in science policy, an adaptive model ensures cultural, moral, and religious views are taken into consideration, thereby building social inclusion. While this ethical consideration by the government may not give a complete voice to every individual, it will help balance policies and maintain the diverse perspectives of those it affects. Embracing an adaptive ethics model of ESC research promotes open-minded dialogue and respect for the importance of human belief and tradition. By actively engaging with cultural and religious values, researchers can better handle disagreements and promote ethical research practices that benefit each society.

This brief exploration of the religious and cultural differences that impact ESC research reveals the nuances of relative ethics and highlights a need for local policymakers to apply a more intense adaptive model.

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[34] Resnik, D. B., Shamoo, A. E., & Krimsky, S. (2006). Fraudulent human embryonic stem cell research in South Korea: lessons learned.  Accountability in research ,  13 (1), 101–109. https://doi.org/10.1080/08989620600634193 .

[35] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6

[36] Association for the Advancement of Blood and Biotherapies.  https://www.aabb.org/regulatory-and-advocacy/regulatory-affairs/regulatory-for-cellular-therapies/international-competent-authorities/saudi-arabia

[37] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia.  BMC medical ethics ,  21 (1), 35. https://doi.org/10.1186/s12910-020-00482-6

[38] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia. BMC medical ethics , 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6

Culturally, autonomy practices follow a relational autonomy approach based on a paternalistic deontological health care model. The adherence to strict international research policies and religious pillars within the regulatory environment is a great foundation for research ethics. However, there is a need to develop locally targeted ethics approaches for research (as called for in Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6), this decision-making approach may help advise a research decision model. For more on the clinical cultural autonomy approaches, see: Alabdullah, Y. Y., Alzaid, E., Alsaad, S., Alamri, T., Alolayan, S. W., Bah, S., & Aljoudi, A. S. (2022). Autonomy and paternalism in Shared decision‐making in a Saudi Arabian tertiary hospital: A cross‐sectional study. Developing World Bioethics , 23 (3), 260–268. https://doi.org/10.1111/dewb.12355 ; Bukhari, A. A. (2017). Universal Principles of Bioethics and Patient Rights in Saudi Arabia (Doctoral dissertation, Duquesne University). https://dsc.duq.edu/etd/124; Ladha, S., Nakshawani, S. A., Alzaidy, A., & Tarab, B. (2023, October 26). Islam and Bioethics: What We All Need to Know . Columbia University School of Professional Studies. https://sps.columbia.edu/events/islam-and-bioethics-what-we-all-need-know

[39] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics.  Research Ethics ,  17 (2), 228-241.  https://doi.org/10.1177/1747016120966779

[40] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics.  Research Ethics ,  17 (2), 228-241.  https://doi.org/10.1177/1747016120966779

[41] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[42] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[43] The EU’s definition of autonomy relates to the capacity for creating ideas, moral insight, decisions, and actions without constraint, personal responsibility, and informed consent. However, the EU views autonomy as not completely able to protect individuals and depends on other principles, such as dignity, which “expresses the intrinsic worth and fundamental equality of all human beings.” Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

[44] Council of Europe. Convention for the protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No. 164) https://www.coe.int/en/web/conventions/full-list?module=treaty-detail&treatynum=164 (forbidding the creation of embryos for research purposes only, and suggests embryos in vitro have protections.); Also see Drabiak-Syed B. K. (2013). New President, New Human Embryonic Stem Cell Research Policy: Comparative International Perspectives and Embryonic Stem Cell Research Laws in France.  Biotechnology Law Report ,  32 (6), 349–356. https://doi.org/10.1089/blr.2013.9865

[45] Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

[46] Tomuschat, C., Currie, D. P., Kommers, D. P., & Kerr, R. (Trans.). (1949, May 23). Basic law for the Federal Republic of Germany. https://www.btg-bestellservice.de/pdf/80201000.pdf

[47] Regulation of Stem Cell Research in Germany . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-germany

[48] Regulation of Stem Cell Research in Finland . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-finland

[49] Regulation of Stem Cell Research in Spain . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-spain

[50] Some sources to consider regarding ethics models or regulatory oversights of other cultures not covered:

Kara MA. Applicability of the principle of respect for autonomy: the perspective of Turkey. J Med Ethics. 2007 Nov;33(11):627-30. doi: 10.1136/jme.2006.017400. PMID: 17971462; PMCID: PMC2598110.

Ugarte, O. N., & Acioly, M. A. (2014). The principle of autonomy in Brazil: one needs to discuss it ...  Revista do Colegio Brasileiro de Cirurgioes ,  41 (5), 374–377. https://doi.org/10.1590/0100-69912014005013

Bharadwaj, A., & Glasner, P. E. (2012). Local cells, global science: The rise of embryonic stem cell research in India . Routledge.

For further research on specific European countries regarding ethical and regulatory framework, we recommend this database: Regulation of Stem Cell Research in Europe . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-europe   

[51] Klitzman, R. (2006). Complications of culture in obtaining informed consent. The American Journal of Bioethics, 6(1), 20–21. https://doi.org/10.1080/15265160500394671 see also: Ekmekci, P. E., & Arda, B. (2017). Interculturalism and Informed Consent: Respecting Cultural Differences without Breaching Human Rights.  Cultura (Iasi, Romania) ,  14 (2), 159–172.; For why trust is important in research, see also: Gray, B., Hilder, J., Macdonald, L., Tester, R., Dowell, A., & Stubbe, M. (2017). Are research ethics guidelines culturally competent?  Research Ethics ,  13 (1), 23-41.  https://doi.org/10.1177/1747016116650235

[52] The Qur'an  (M. Khattab, Trans.). (1965). Al-Mu’minun, 23: 12-14. https://quran.com/23

[53] Lenfest, Y. (2017, December 8). Islam and the beginning of human life . Bill of Health. https://blog.petrieflom.law.harvard.edu/2017/12/08/islam-and-the-beginning-of-human-life/

[54] Aksoy, S. (2005). Making regulations and drawing up legislation in Islamic countries under conditions of uncertainty, with special reference to embryonic stem cell research. Journal of Medical Ethics , 31: 399-403.; see also: Mahmoud, Azza. "Islamic Bioethics: National Regulations and Guidelines of Human Stem Cell Research in the Muslim World." Master's thesis, Chapman University, 2022. https://doi.org/10.36837/ chapman.000386

[55] Rashid, R. (2022). When does Ensoulment occur in the Human Foetus. Journal of the British Islamic Medical Association , 12 (4). ISSN 2634 8071. https://www.jbima.com/wp-content/uploads/2023/01/2-Ethics-3_-Ensoulment_Rafaqat.pdf.

[56] Sivaraman, M. & Noor, S. (2017). Ethics of embryonic stem cell research according to Buddhist, Hindu, Catholic, and Islamic religions: perspective from Malaysia. Asian Biomedicine,8(1) 43-52.  https://doi.org/10.5372/1905-7415.0801.260

[57] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[58] Lecso, P. A. (1991). The Bodhisattva Ideal and Organ Transplantation.  Journal of Religion and Health ,  30 (1), 35–41. http://www.jstor.org/stable/27510629 ; Bodhisattva, S. (n.d.). The Key of Becoming a Bodhisattva . A Guide to the Bodhisattva Way of Life. http://www.buddhism.org/Sutras/2/BodhisattvaWay.htm

[59] There is no explicit religious reference to when life begins or how to conduct research that interacts with the concept of life. However, these are relevant verses pertaining to how the fetus is viewed. (( King James Bible . (1999). Oxford University Press. (original work published 1769))

Jerimiah 1: 5 “Before I formed thee in the belly I knew thee; and before thou camest forth out of the womb I sanctified thee…”

In prophet Jerimiah’s insight, God set him apart as a person known before childbirth, a theme carried within the Psalm of David.

Psalm 139: 13-14 “…Thou hast covered me in my mother's womb. I will praise thee; for I am fearfully and wonderfully made…”

These verses demonstrate David’s respect for God as an entity that would know of all man’s thoughts and doings even before birth.

[60] It should be noted that abortion is not supported as well.

[61] The Vatican. (1987, February 22). Instruction on Respect for Human Life in Its Origin and on the Dignity of Procreation Replies to Certain Questions of the Day . Congregation For the Doctrine of the Faith. https://www.vatican.va/roman_curia/congregations/cfaith/documents/rc_con_cfaith_doc_19870222_respect-for-human-life_en.html

[62] The Vatican. (2000, August 25). Declaration On the Production and the Scientific and Therapeutic Use of Human Embryonic Stem Cells . Pontifical Academy for Life. https://www.vatican.va/roman_curia/pontifical_academies/acdlife/documents/rc_pa_acdlife_doc_20000824_cellule-staminali_en.html ; Ohara, N. (2003). Ethical Consideration of Experimentation Using Living Human Embryos: The Catholic Church’s Position on Human Embryonic Stem Cell Research and Human Cloning. Department of Obstetrics and Gynecology . Retrieved from https://article.imrpress.com/journal/CEOG/30/2-3/pii/2003018/77-81.pdf.

[63] Smith, G. A. (2022, May 23). Like Americans overall, Catholics vary in their abortion views, with regular mass attenders most opposed . Pew Research Center. https://www.pewresearch.org/short-reads/2022/05/23/like-americans-overall-catholics-vary-in-their-abortion-views-with-regular-mass-attenders-most-opposed/

[64] Rosner, F., & Reichman, E. (2002). Embryonic stem cell research in Jewish law. Journal of halacha and contemporary society , (43), 49–68.; Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[65] Schenker J. G. (2008). The beginning of human life: status of embryo. Perspectives in Halakha (Jewish Religious Law).  Journal of assisted reproduction and genetics ,  25 (6), 271–276. https://doi.org/10.1007/s10815-008-9221-6

[66] Ruttenberg, D. (2020, May 5). The Torah of Abortion Justice (annotated source sheet) . Sefaria. https://www.sefaria.org/sheets/234926.7?lang=bi&with=all&lang2=en

[67] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[68] Gert, B. (2007). Common morality: Deciding what to do . Oxford Univ. Press.

[69] World Medical Association (2013). World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA , 310(20), 2191–2194. https://doi.org/10.1001/jama.2013.281053 Declaration of Helsinki – WMA – The World Medical Association .; see also: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979).  The Belmont report: Ethical principles and guidelines for the protection of human subjects of research . U.S. Department of Health and Human Services.  https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html

[70] Zakarin Safier, L., Gumer, A., Kline, M., Egli, D., & Sauer, M. V. (2018). Compensating human subjects providing oocytes for stem cell research: 9-year experience and outcomes.  Journal of assisted reproduction and genetics ,  35 (7), 1219–1225. https://doi.org/10.1007/s10815-018-1171-z https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063839/ see also: Riordan, N. H., & Paz Rodríguez, J. (2021). Addressing concerns regarding associated costs, transparency, and integrity of research in recent stem cell trial. Stem Cells Translational Medicine , 10 (12), 1715–1716. https://doi.org/10.1002/sctm.21-0234

[71] Klitzman, R., & Sauer, M. V. (2009). Payment of egg donors in stem cell research in the USA.  Reproductive biomedicine online ,  18 (5), 603–608. https://doi.org/10.1016/s1472-6483(10)60002-8

[72] Krosin, M. T., Klitzman, R., Levin, B., Cheng, J., & Ranney, M. L. (2006). Problems in comprehension of informed consent in rural and peri-urban Mali, West Africa.  Clinical trials (London, England) ,  3 (3), 306–313. https://doi.org/10.1191/1740774506cn150oa

[73] Veatch, Robert M.  Hippocratic, Religious, and Secular Medical Ethics: The Points of Conflict . Georgetown University Press, 2012.

[74] Msoroka, M. S., & Amundsen, D. (2018). One size fits not quite all: Universal research ethics with diversity.  Research Ethics ,  14 (3), 1-17.  https://doi.org/10.1177/1747016117739939

[75] Pirzada, N. (2022). The Expansion of Turkey’s Medical Tourism Industry.  Voices in Bioethics ,  8 . https://doi.org/10.52214/vib.v8i.9894

[76] Stem Cell Tourism: False Hope for Real Money . Harvard Stem Cell Institute (HSCI). (2023). https://hsci.harvard.edu/stem-cell-tourism , See also: Bissassar, M. (2017). Transnational Stem Cell Tourism: An ethical analysis.  Voices in Bioethics ,  3 . https://doi.org/10.7916/vib.v3i.6027

[77] Song, P. (2011) The proliferation of stem cell therapies in post-Mao China: problematizing ethical regulation,  New Genetics and Society , 30:2, 141-153, DOI:  10.1080/14636778.2011.574375

[78] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[79] International Society for Stem Cell Research. (2024). Standards in stem cell research . International Society for Stem Cell Research. https://www.isscr.org/guidelines/5-standards-in-stem-cell-research

[80] Benjamin, R. (2013). People’s science bodies and rights on the Stem Cell Frontier . Stanford University Press.

Mifrah Hayath

SM Candidate Harvard Medical School, MS Biotechnology Johns Hopkins University

Olivia Bowers

MS Bioethics Columbia University (Disclosure: affiliated with Voices in Bioethics)

Article Details

This work is licensed under a Creative Commons Attribution 4.0 International License .

Innovative USask 'mini-brains' could revolutionize Alzheimer’s treatment

Using an innovative new method, a University of Saskatchewan (USask) researcher is building tiny pseudo-organs from stem cells to help diagnose and treat Alzheimer’s.

May 14, 2024

When Dr. Tyler Wenzel (PhD) first came up with the idea of building a miniature brain from stem cells, he never could have predicted how well his creations would work.

Now, Wenzel’s “mini-brain” could revolutionize the way Alzheimer’s and other brain-related diseases are diagnosed and treated.

“Never in our wildest dreams did we think that our crazy idea would work,” he said. “These could be used as a diagnostic tool, built from blood.”

Wenzel, a postdoctoral fellow in the College of Medicine’s Department of Psychiatry, developed the idea for the “mini-brain” - or more formally, a one-of-a-kind cerebral organoid model – while working under the supervision of Dr. Darrell Mousseau (PhD).

Human stem cells can be manipulated to develop into practically any other cell in the body. Using stem cells taken from human blood, Wenzel was able to create a tiny artificial organ – roughly three millimetres across and resembling visually what Wenzel described as a piece of chewed gum someone has tried to smooth out again.

These “mini-brains” are built by creating stem cells from a blood sample, and then transforming these stem cells into functioning brain cells. Using small synthetic organoids for research is not a novel concept – but the “mini-brains” developed in Wenzel’s lab are unique. As outlined in Wenzel’s recent published article in Frontiers of Cellular Neuroscience , the brains from Wenzel’s lab are comprised of four different types of brain cells while most brain organoids are comprised of only neurons.

In testing, Wenzel's "mini-brains" more accurately reflect a fully-fledged adult human brain, so they can be used to more closely examine neurological conditions of adult patients, such as Alzheimer disease.

And for those “mini-brains” created from the stem cells of individuals who have Alzheimer’s, Wenzel determined that the artificial organ displayed the pathology of Alzheimer’s – just on a smaller scale.

“If stem cells have the capacity to become any cell in the human body, the question then came ‘could we create something that resembles an entire organ?’” Wenzel said. “While we were developing it, I had the crazy idea that if these truly are human brains, if a patient had a disease like Alzheimer’s and we grew their ‘mini-brain,’ in theory that tiny brain would have Alzheimer’s.”

Wenzel said this technology has the potential to change the way health services are provided to those with Alzheimer’s, particularly in rural and remote communities. This groundbreaking research has already received support from the Alzheimer Society of Canada.

If Wenzel and his colleagues can create a consistent way to diagnose and treat neurological conditions like Alzheimer’s using only a small blood sample – which has a relatively long shelf life and can be couriered – instead of requiring patients to travel to hospitals or specialized clinics, it could be a tremendous resource savings for the healthcare system and a burden off of patients.

“In theory, if this tool works the way we think it does, we could just get a blood sample shipped from La Loche or La Ronge to the university and diagnose you like that,” he said.

The early proof-of-concept work on the “mini-brains” has been extremely promising – which means the next step for Wenzel is expanding the testing to a larger pool of patients.

The researchers are also interested in trying to expand the scope of the “mini-brain” research. According to Wenzel, if they can confirm the “mini-brains” accurately reflect other brain diseases or neurological conditions, they could potentially be used to speed up diagnoses or test the efficacy of drugs on patients.

As an example, Wenzel pointed to the substantial wait times to see a psychiatrist in Saskatchewan. If the “mini-brains” could be used to test which antidepressant works best on a patient suffering from depression, it could dramatically reduce the time required to see a doctor and receive a prescription.

A former high school science teacher who made the move into the world of research and academia, Wenzel said it’s the “nature of research” to come up with a hypothesis and hit close to the mark in an experiment that excites him his work.

The astounding success of the early “mini-brains,” however, has been so staggering that Wenzel admitted he still struggles to wrap his own brain around it.

“I’m still in disbelief, but it’s also extremely motivating that something like this happened,” Wenzel said. “It gives me something that I think will impact society and have actual relevance and create some change … it has a strong potential to shift the landscape of medicine.”

Together, we will undertake the research the world needs. We invite you to join by  supporting critical research  at USask.

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• Review Article
• Published: 14 May 2024

Challenges and perspectives of heart repair with pluripotent stem cell-derived cardiomyocytes

• Thomas Eschenhagen   ORCID: orcid.org/0000-0003-1750-1170 1 , 2 &
• Florian Weinberger 1 , 2 , 3  

Nature Cardiovascular Research volume  3 ,  pages 515–524 ( 2024 ) Cite this article

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• Cardiac regeneration
• Myocardial infarction

Here we aim at providing a concise but comprehensive overview of the perspectives and challenges of heart repair with pluripotent stem cell-derived cardiomyocytes. This Review comes at a time when consensus has been reached about the lack of relevant proliferative capacity of adult mammalian cardiomyocytes and the lack of new heart muscle formation with autologous cell sources. While alternatives to cell-based approaches will be shortly summarized, the focus lies on pluripotent stem cell-derived cardiomyocyte repair, which entered first clinical trials just 2 years ago. In the view of the authors, these early trials are important but have to be viewed as early proof-of-concept trials in humans that will hopefully provide first answers on feasibility, safety and the survival of allogeneic pluripotent stem cell-derived cardiomyocyte in the human heart. Better approaches have to be developed to make this approach clinically applicable.

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Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

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Acknowledgements

Our work on this topic was supported by a Late Translational Research Grant from the German Centre for Cardiovascular Research (DZHK), (81×2710153 to T.E.), the European Research Council (ERC-AG IndivuHeart to T.E.), the German Research Foundation (DFG, WE5620/3-1 to F.W. and T.E.) and the Werner Otto Stiftung (F.W.). Additionally, we have received funding from the European Union’s Horizon 2020 research and innovation program (874764 to T.E.) and the European Union’s Horizon 2020 FetOpen RIA (964800; to F.W.).

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Eschenhagen, T., Weinberger, F. Challenges and perspectives of heart repair with pluripotent stem cell-derived cardiomyocytes. Nat Cardiovasc Res 3 , 515–524 (2024). https://doi.org/10.1038/s44161-024-00472-6

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On March 9, 2009, President Barack Obama lifted, by Executive Order , the Bush administration's eight-year ban on federal funding of embryonic stem cell research .

Remarked the President, "Today... we will bring the change that so many scientists and researchers, doctors and innovators, patients and loved ones have hoped for, and fought for, these past eight years."

In Obama's Remarks on Lifting the Embryonic Stem Cell Research Ban, he also signed a Presidential Memorandum directing the development of a strategy for restoring scientific integrity to government decision-making.

Bush Vetoes

In 2005, H.R. 810, the Stem Cell Research Enhancement Act of 2005, was passed by the Republican-led House in May 2005 by a vote of 238 to 194. The Senate passed the bill in July 2006 by a bipartisan vote of 63 to 37.

President Bush opposed embryonic stem cell research on ideological grounds. He exercised his first presidential veto on July 19, 2006, when he refused to allow H.R. 810 to become law. Congress was unable to muster enough votes to override the veto.

In April 2007, the Democratic-led Senate passed the Stem Cell Research Enhancement Act of 2007 by a vote of 63 to 34. In June 2007, the House passed the legislation by a vote of 247 to 176.

President Bush vetoed the bill on June 20, 2007.

Public Support for Embryonic Stem Cell Research

For years, all polls report that the American public STRONGLY supports federal funding of embryonic stem cell research.

Reported the Washington Post in March 2009 : "In a January Washington Post-ABC News poll, 59 percent of Americans said they supported loosening the current restrictions, with support topping 60 percent among both Democrats and independents. Most Republicans, however, stood in opposition (55 percent opposed; 40 percent in support)."

Despite public perceptions, embryonic stem cell research was legal in the U.S. during the Bush administration: the President had banned the use of federal funds for research. He did not ban private and state research funding, much of which was being conducted by pharmaceutical mega-corporations.

In Fall 2004, California voters approved a $3 billion bond to fund embryonic stem cell research. In contrast, embryonic stem cell research is prohibited in Arkansas, Iowa, North and South Dakota and Michigan.

Developments in Stem Cell Research

In August 2005, Harvard University scientists announced a breakthrough discovery that fuses "blank" embryonic stem cells with adult skin cells, rather than with fertilized embryos, to create all-purpose stem cells viable to treat diseases and disabilities.

This discovery doesn't result in the death of fertilized human embryos and thus would effectively respond to pro-life objections to embryonic stem cell research and therapy.

Harvard researchers warned that it could take up to ten years to perfect this highly promising process.

As South Korea, Great Britain, Japan, Germany, India and other countries rapidly pioneer this new technological frontier, the US is being left farther and farther behind in medical technology. The US is also losing out on billions in new economic opportunities at a time when the country sorely needs new sources of revenues.

Therapeutic cloning is a method to produce stem cell lines that were genetic matches for adults and children.

Steps in therapeutic cloning are:

• An egg is obtained from a human donor.
• The nucleus (DNA) is removed from the egg.
• Skin cells are taken from the patient.
• The nucleus (DNA) is removed from a skin cell.
• A skin cell nucleus is implanted in the egg.
• The reconstructed egg, called a blastocyst, is stimulated with chemicals or electric current.
• In 3 to 5 days, the embryonic stem cells are removed.
• The blastocyst is destroyed.
• Stem cells can be used to generate an organ or tissue that is a genetic match to the skin cell donor.

The first 6 steps are same for reproductive cloning . However, instead of removing stem cells, the blastocyst is implanted in a woman and allowed to gestate to birth. Reproductive cloning is outlawed in most countries.

Before Bush stopped federal research in 2001, a minor amount of embryonic stem cell research was performed by US scientists using embryos created at fertility clinics and donated by couples who no longer needed them. The pending bipartisan Congressional bills all propose using excess fertility clinic embryos.

Stem cells are found in limited quantities in every human body and can be extracted from adult tissue with great effort but without harm. The consensus among researchers has been that adult stem cells are limited in usefulness because they can be used to produce only a few of the 220 types of cells found in the human body. However, evidence has recently emerged that adult cells may be more flexible than previously believed.

Embryonic stem cells are blank cells that have not yet been categorized or programmed by the body and can be prompted to generate any of the 220 human cell types. Embryonic stem cells are extremely flexible.

Embryonic stem cells are thought by most scientists and researchers to hold potential cures for spinal cord injuries, multiple sclerosis, diabetes, Parkinson's disease, cancer, Alzheimer's disease, heart disease, hundreds of rare immune system and genetic disorders and much more.

Scientists see almost infinite value in the use of embryonic stem cell research to understand human development and the growth and treatment of diseases.

Actual cures are many years away, though, since research has not progressed to the point where even one cure has yet been generated by embryonic stem cell research.

Over 100 million Americans suffer from diseases that eventually may be treated more effectively or even cured with embryonic stem cell therapy. Some researchers regard this as the greatest potential for the alleviation of human suffering since the advent of antibiotics.

Many pro-lifers believe that the proper moral and religious course of action is to save existing life through embryonic stem cell therapy.

Some staunch pro-lifers and most pro-life organizations regard the destruction of the blastocyst, which is a laboratory-fertilized human egg, to be the murder of human life. They believe that life begins at conception, and that destruction of this pre-born life is morally unacceptable.

They believe that it is immoral to destroy a few-days-old human embryo, even to save or reduce suffering in existing human life.

Many also believe that insufficient attention been given to explore the potential of adult stem cells, which have already been used to successfully cure many diseases. They also argue that too little attention has been paid to the potential of umbilical cord blood for stem cell research. They also point out that no cures have yet been produced by embryonic stem cell therapy.

At every step of the embryonic stem cell therapy process, decisions are made by scientists, researchers, medical professionals and women who donate eggs...decisions that are fraught with serious ethical and moral implications. Those against embryonic stem cell research argue that funding should be used to greatly expand adult stem research, to circumvent the many moral issues involving the use of human embryos.

Lifting the Ban

Now that President Obama has lifted the federal funding ban for embryonic stem cell research, financial support will soon flow to federal and state agencies to commence the necessary scientific research. The timeline for therapeutic solutions available to all Americans could be years away.

President Obama observed on March 9, 2009, when he lifted the ban:

"Medical miracles do not happen simply by accident. They result from painstaking and costly research, from years of lonely trial and error, much of which never bears fruit, and from a government willing to support that work...

"Ultimately, I cannot guarantee that we will find the treatments and cures we seek. No President can promise that.

"But I can promise that we will seek them -- actively, responsibly, and with the urgency required to make up for lost ground."

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