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Stem cells: what they are and what they do.

Stem cells offer promise for new medical treatments. Learn about stem cell types, current and possible uses, and the state of research and practice.

You've heard about stem cells in the news, and perhaps you've wondered if they might help you or a loved one with a serious disease. Here are some answers to frequently asked questions about stem cells.

What are stem cells?

Stem cells: The body's master cells

Stem cells are the body's master cells. All other cells arise from stem cells, including blood cells, nerve cells and other cells.

Stem cells are a special type of cells that have two important properties. They are able to make more cells like themselves. That is, they self-renew. And they can become other cells that do different things in a process known as differentiation. Stem cells are found in almost all tissues of the body. And they are needed for the maintenance of tissue as well as for repair after injury.

Depending on where the stem cells are, they can develop into different tissues. For example, hematopoietic stem cells reside in the bone marrow and can produce all the cells that function in the blood. Stem cells also can become brain cells, heart muscle cells, bone cells or other cell types.

There are various types of stem cells. Embryonic stem cells are the most versatile since they can develop into all the cells of the developing fetus. The majority of stem cells in the body have fewer abilities to give rise to cells and may only help maintain and repair the tissues and organs in which they reside.

No other cell in the body has the natural ability to generate new cell types.

Why is there such an interest in stem cells?

Researchers are studying stem cells to see if they can help to:

• Increase understanding of how diseases occur. By watching stem cells mature into cells in bones, heart muscle, nerves, and other organs and tissue, researchers may better understand how diseases and conditions develop.

Generate healthy cells to replace cells affected by disease (regenerative medicine). Stem cells can be guided into becoming specific cells that can be used in people to regenerate and repair tissues that have been damaged or affected by disease.

People who might benefit from stem cell therapies include those with leukemia, Hodgkin disease, non-Hodgkin lymphoma and some solid tumor cancers. Stem cell therapies also might benefit people who have aplastic anemia, immunodeficiencies and inherited conditions of metabolism.

Stem cells are being studied to treat type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, heart failure, osteoarthritis and other conditions.

Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine.

Test new drugs for safety and effectiveness. Before giving drugs in development to people, researchers can use some types of stem cells to test the drugs for safety and quality. This type of testing may help assess drugs in development for toxicity to the heart.

New areas of study include the effectiveness of using human stem cells that have been programmed into tissue-specific cells to test new drugs. For the testing of new drugs to be accurate, the cells must be programmed to acquire properties of the type of cells targeted by the drug. Techniques to program cells into specific cells are under study.

Where do stem cells come from?

There are several sources of stem cells:

Embryonic stem cells. These stem cells come from embryos that are 3 to 5 days old. At this stage, an embryo is called a blastocyst and has about 150 cells.

These are pluripotent (ploo-RIP-uh-tunt) stem cells, meaning they can divide into more stem cells or can become any type of cell in the body. This allows embryonic stem cells to be used to regenerate or repair diseased tissue and organs.

• Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow or fat. Compared with embryonic stem cells, adult stem cells have a more limited ability to give rise to various cells of the body.

Adult cells altered to have properties of embryonic stem cells. Scientists have transformed regular adult cells into stem cells using genetic reprogramming. By altering the genes in the adult cells, researchers can make the cells act similarly to embryonic stem cells. These cells are called induced pluripotent stem cells (iPSCs).

This new technique may allow use of reprogrammed cells instead of embryonic stem cells and prevent immune system rejection of the new stem cells. However, scientists don't yet know whether using altered adult cells will cause adverse effects in humans.

Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells had better heart function and survival time.

Perinatal stem cells. Researchers have discovered stem cells in amniotic fluid as well as umbilical cord blood. These stem cells can change into specialized cells.

Amniotic fluid fills the sac that surrounds and protects a developing fetus in the uterus. Researchers have identified stem cells in samples of amniotic fluid drawn from pregnant women for testing or treatment — a procedure called amniocentesis.

Why is there controversy about using embryonic stem cells?

The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research and include recommendations for the donation of embryonic stem cells. Also, the guidelines state that embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.

Where do these embryos come from?

The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in women's uteruses. The stem cells are donated with informed consent from donors. The stem cells can live and grow in special solutions in test tubes or petri dishes in laboratories.

Why can't researchers use adult stem cells instead?

Progress in cell reprogramming and the formation of iPSCs has greatly enhanced research in this field. However, reprogramming is an inefficient process. When possible, iPSCs are used instead of embryonic stem cells since this avoids the ethical issues about use of embryonic stem cells that may be morally objectionable for some people.

Although research into adult stem cells is promising, adult stem cells may not be as versatile and durable as are embryonic stem cells. Adult stem cells may not be able to be manipulated to produce all cell types, which limits how adult stem cells can be used to treat diseases.

Adult stem cells are also more likely to contain irregularities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, researchers have found that adult stem cells are more adaptable than was first thought.

What are stem cell lines, and why do researchers want to use them?

A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don't become specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.

What is stem cell therapy (regenerative medicine), and how does it work?

Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next chapter in organ transplantation and uses cells instead of donor organs, which are limited in supply.

Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells.

The specialized cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the heart muscle. The healthy transplanted heart muscle cells could then contribute to repairing the injured heart muscle.

Researchers have already shown that adult bone marrow cells guided to become heart-like cells can repair heart tissue in people, and more research is ongoing.

Have stem cells already been used to treat diseases?

Yes. Doctors have performed stem cell transplants, also known as bone marrow transplants, for many decades. In hematopoietic stem cell transplants, stem cells replace cells damaged by chemotherapy or disease or serve as a way for the donor's immune system to fight some types of cancer and blood-related diseases. Leukemia, lymphoma, neuroblastoma and multiple myeloma often are treated this way. These transplants use adult stem cells or umbilical cord blood.

Researchers are testing adult stem cells to treat other conditions, including some degenerative diseases such as heart failure.

What are the potential problems with using embryonic stem cells in humans?

For embryonic stem cells to be useful, researchers must be certain that the stem cells will differentiate into the specific cell types desired.

Researchers have discovered ways to direct stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. Research is ongoing in this area.

Embryonic stem cells also can grow irregularly or specialize in different cell types spontaneously. Researchers are studying how to control the growth and development of embryonic stem cells.

Embryonic stem cells also might trigger an immune response in which the recipient's body attacks the stem cells as foreign invaders, or the stem cells might simply fail to function as expected, with unknown consequences. Researchers continue to study how to avoid these possible complications.

What is therapeutic cloning, and what benefits might it offer?

Therapeutic cloning, also called somatic cell nuclear transfer, is a way to create versatile stem cells independent of fertilized eggs. In this technique, the nucleus is removed from an unfertilized egg. This nucleus contains the genetic material. The nucleus also is removed from the cell of a donor.

This donor nucleus is then injected into the egg, replacing the nucleus that was removed, in a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This process creates a line of stem cells that is genetically identical to the donor's cells — in essence, a clone.

Some researchers believe that stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because cloned cells are less likely to be rejected once transplanted back into the donor. And it may allow researchers to see exactly how a disease develops.

Has therapeutic cloning in people been successful?

No. Researchers haven't been able to successfully perform therapeutic cloning with humans despite success in a number of other species.

Researchers continue to study the potential of therapeutic cloning in people.

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• Stem cell basics. National Institutes of Health. https://stemcells.nih.gov/info/basics/stc-basics/#stc-I. Accessed March 21, 2024.
• Lovell-Badge R, et al. ISSCR guidelines for stem cell research and clinical translation: The 2021 update. Stem Cell Reports. 2021; doi:10.1016/j.stemcr.2021.05.012.
• AskMayoExpert. Hematopoietic stem cell transplant. Mayo Clinic; 2024.
• Stem cell transplants in cancer treatment. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant/. Accessed March 21, 2024.
• Townsend CM Jr, et al. Regenerative medicine. In: Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 21st ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed March 21, 2024.
• Kumar D, et al. Stem cell based preclinical drug development and toxicity prediction. Current Pharmaceutical Design. 2021; doi:10.2174/1381612826666201019104712.
• NIH guidelines for human stem cell research. National Institutes of Health. https://stemcells.nih.gov/research-policy/guidelines-for-human-stem-cell-research. Accessed March 21, 2024.
• De la Torre P, et al. Current status and future prospects of perinatal stem cells. Genes. 2020; doi:10.3390/genes12010006.
• Yen Ling Wang A. Human induced pluripotent stem cell-derived exosomes as a new therapeutic strategy for various diseases. International Journal of Molecular Sciences. 2021; doi:10.3390/ijms22041769.
• Alessandrini M, et al. Stem cell therapy for neurological disorders. South African Medical Journal. 2019; doi:10.7196/SAMJ.2019.v109i8b.14009.
• Goldenberg D, et al. Regenerative engineering: Current applications and future perspectives. Frontiers in Surgery. 2021; doi:10.3389/fsurg.2021.731031.
• Brown MA, et al. Update on stem cell technologies in congenital heart disease. Journal of Cardiac Surgery. 2020; doi:10.1111/jocs.14312.
• Li M, et al. Brachyury engineers cardiac repair competent stem cells. Stem Cells Translational Medicine. 2021; doi:10.1002/sctm.20-0193.
• Augustine R, et al. Stem cell-based approaches in cardiac tissue engineering: Controlling the microenvironment for autologous cells. Biomedical Pharmacotherapy. 2021; doi:10.1016/j.biopha.2021.111425.
• Cloning fact sheet. National Human Genome Research Institute. https://www.genome.gov/about-genomics/fact-sheets/Cloning-Fact-Sheet. Accessed March 21, 2024.
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November 16, 2022

Putting Stem Cell-Based Therapies in Context

Karen M. Wai, MD, Theodore Leng, MD, MS, and Jeffrey Goldberg, MD, PhD, Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, CA

In recent years, the potential of stem cell-based therapies to treat a wide range of medical conditions has given hope to patients in search of novel treatments or cures. At the same time, thousands of rogue clinics have sprung up across the U.S and around the world, offering stem cell-based therapies before being tested for safety and efficacy. When communicating to the public about stem cell-based therapies, it is important to put any treatment claims in context.

Stem cell-based therapies include any treatment that uses human stem cells. These cells have the potential to develop into many different types of cells in the body. They offer a theoretically unlimited source of repair cells and/or tissues. (For more about stem cells, see  https://stemcells.nih.gov .)

Over the past three decades, the Food and Drug Administration (FDA) has approved several stem cell-based products. These include bone marrow transplants, which have been transformational for many cancer patients, and therapies for blood and immune system disorders. 1 Other approved treatments include dental uses for gum and tissue growth and in skin for burns. Since the early 2000s, stem cell-based therapies have been explored in many eye diseases, including age-related macular degeneration and glaucoma. 2 Stem cell-based therapies are also being explored for neurodegenerative diseases such as stroke and Alzheimer’s disease, and for countless other conditions.

Over time, we expect that breakthroughs will continue with stem cell-based therapies for many conditions. However, at this time, rogue clinics, driven by profits, are taking advantage of patients desperate for cures and are claiming dramatic results, often exaggerated in sensational media testimonials. The clinics may mimic legitimate practices. They may extract a patient’s own stem cells, concentrate or modify the cells, and then re-inject them. Some manufacturers offer stem cell-based derived products, such as “biologic eye drops” made with placenta extract or amniotic fluid to treat dry eye. Clinics may provide misleading information and advertise their practice as running clinical trials. However, these clinics almost always work without FDA regulatory approval and outside of legitimate clinical trial approaches.

These unproven, unregulated stem cell treatments carry significant risk. The risks range from administration site reactions to dangerous adverse events. For example, injected cells can multiply into inappropriate cell types or even dangerous tumors. A 2017 report described one Florida clinic that blinded patients with stem cell eye injections. 3

The Pew Charitable Trusts gathered 360 reports of adverse events related to unapproved stem cell therapies, including 20 cases that caused death. 4 Further, adverse events are likely underreported because these products are not FDA approved or regulated. Many unproven stem cell-based therapies cost thousands of dollars to patients and are not covered by insurance. Further, even if patients avoid adverse events from these therapies, they may suffer consequences from delaying evidence-based treatments.

The FDA has made substantial progress toward regulation of stem cell-based therapies. In 2017, it released guidance under the 21 st Century Cures Act that clarifies which stem-cell based therapies fall under FDA regulation. It also better defined how the agency will act against unsafe or unregulated products. 5 As of May 2021, the FDA has more strongly enforced compliance for clinics that continue to market unproven treatments. 6

Despite this increased regulation, rogue clinics are still relatively commonplace. A 2021 study estimated that there are over 2,500 U.S. clinics selling unproven stem cell treatments. 7  Patients at these clinics are often led to believe that treatments are either approved by the FDA, registered with the FDA, or do not require FDA approval. It is important to recognize that there are limits to the FDA’s expanded reach, especially when it is targeting hundreds of clinics at once. Our clinic at Stanford recently cared for a patient who had received stem cell injections behind his eyes, where he developed tumors that ultimately ruined vision in both eyes.

Progress in stem cell science is rapidly translating to the clinic, but it is not yet the miracle answer we envision. With time, stem cell-based therapies will likely expand treatment options. People considering a stem-cell based therapy should find out if a treatment is FDA-approved or being studied under an FDA-approved clinical investigation plan. This is called an Investigational New Drug Application. Importantly, being registered with ClinicalTrials.gov does not mean that a therapy or clinical study has been authorized or reviewed by the FDA. For more information about stem cell therapies, visit www.closerlookatstemcells.org , a resource from the International Society for Stem Cell Research.

As we look hopefully to the future, we need greater awareness of the current limitations of stem cell therapy and the dangers posed by unregulated stem cell clinics. Strong FDA regulation and oversight are important for ensuring that stem cell-based therapies are safe and effective for patients. Accurate communication to the public, careful advocacy by physicians, and education of patients all continue to be crucial.

References :

1 U.S. Food and Drug Administration, “Approved Cellular and Gene Therapy Products,” Sept. 9, 2022,  https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products .

2 Stern JH, Tian Y, Funderburgh J, Pellegrini G, Zhang K, Goldberg JL, Ali RR, Young M, Xie Y, Temple S. Regenerating Eye Tissues to Preserve and Restore Vision. Cell Stem Cell . 2018 Sep 6;23(3):453. doi: 10.1016/j.stem.2018.08.014. Erratum for: Cell Stem Cell. 2018 Jun 1;22(6):834-849. PMID: 30193132.

3 Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, Parrott MB, Rosenfeld PJ, Flynn HW Jr, Goldberg JL. Vision Loss after Intravitreal Injection of Autologous "Stem Cells" for AMD. N Engl J Med . 2017 Mar 16;376(11):1047-1053. doi: 10.1056/NEJMoa1609583. PMID: 28296617; PMCID: PMC5551890.

4 The Pew Charitable Trusts, “Harms Linked to Unapproved Stem Cell Interventions Highlight Need for Greater FDA Enforcement,” June 1, 2021,  https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2021/06/harms-linked-to-unapproved-stem-cell-interventions-highlight-need-for-greater-fda-enforcement .

5 U.S. Food and Drug Administration, “FDA announces comprehensive regenerative medicine policy framework,” Feb. 2, 2022,  https://www.fda.gov/news-events/press-announcements/fda-announces-comprehensive-regenerative-medicine-policy-framework .

6  U.S. Food and Drug Administration, “FDA Extends Enforcement Discretion Policy for Certain Regenerative Medicine Products,” July 7, 2020,  https://www.fda.gov/news-events/press-announcements/fda-extends-enforcement-discretion-policy-certain-regenerative-medicine-products .

7  Turner L. The American stem cell sell in 2021: U.S. businesses selling unlicensed and unproven stem cell interventions. Cell Stem Cell . 2021 Nov 4;28(11):1891-1895. doi: 10.1016/j.stem.2021.10.008. PMID: 34739831.

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1. What stem cell-based therapies are currently available?

A closer look at stem cells.

You can learn a lot about stem cell research and its potential to impact human health on the website " A Closer Look at Stem Cells ," which is designed, maintained and hosted by the International Society for Stem Cell Research (ISSCR).

This website offers many resources for patients and those looking for more information about stem cell biology and regenerative medicine. It includes information about  what to consider when joining a clinical trial .

Clinical Trials

Currently, the only stem cell-based treatment that is routinely reviewed and approved by the U.S. Food and Drug Administration (FDA) is hematopoietic (or blood) stem cell transplantation. It is used to treat patients with cancers and disorders that affect the blood and immune system.

Stem cell-based therapies for all other conditions are still experimental.

The website ClinicalTrials.gov has the most up-to-date information about clinical trials that are testing whether stem cell-based therapies are safe and effective in humans.

If you have questions about specific clinical trials, the only people who can answer them properly are those who are listed as the primary contact for each study listed on ClinicalTrials.gov.

HSCI does not enroll any volunteers in clinical trials.

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April 29, 2024

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Stem cells improve memory, reduce inflammation in Alzheimer's mouse brains

by Noah Fromson, University of Michigan

When people think of Alzheimer's Disease and possible treatment, amyloid—and the accumulation of plaques that invade the cerebral cortex—is often brought up first. However, scientists are finding that Alzheimer's is influenced by many factors, including neuroinflammation and disrupted metabolism.

By transplanting human neural stem cells, researchers led by Michigan Medicine improved memory and reduced neuroinflammation in a mouse model of Alzheimer's Disease, suggesting another avenue for potential treatment. Their results are published in Frontiers in Aging Neuroscience .

"The beneficial effects of transplanting human neural stem cells within the brains of Alzheimer's Disease mice occurred despite amyloid plaque levels remaining unchanged, which lends further evidence that strategies targeting neuroinflammation may be a promising therapeutic strategy, independent of amyloid plaques ," said lead author Kevin Chen, M.D., clinical assistant professor of neurosurgery and neurology at Michigan Medicine.

"Additionally, the treatment was associated with normalized inflammation in the microglia, which are the innate immune cells of the brain that become activated with Alzheimer's Disease. As the disease progresses, microglia and their inflammatory signaling is thought to contribute to neuron loss."

A team at Michigan Medicine's NeuroNetwork for Emerging Therapies transplanted neural stem cells into the memory centers of transgenic mice that expressed mutations associated with familial Alzheimer's Disease. They had both the test mice and control mice perform a task called the Morris water maze to assess spatial memory and learning eight weeks after transplant.

Investigators found that Alzheimer's disease mice transplanted with stem cells had their learning curves restored to resemble the control mice with normal learning and memory.

Additional testing through spatial transcriptomics—a method to measure gene expression in areas across the brain—revealed more than 1,000 differently expressed genes that were normalized in the memory centers of the Alzheimer's Disease mice after transplantation.

In analyzing the gene expression changes specifically in microglia, the genetic markers linked to progression of Alzheimer's Disease were also restored to levels close to control mice. This suggested a reduction in neuroinflammation and disease progression.

Researchers say the improvements reported after stem cell transplantation must be further studied in mice before advancing to larger animals and, eventually, humans.

"Our research is incredibly important and continues to support the promise of stem cell therapies in neurodegenerative diseases," said senior author Eva Feldman, M.D., Ph.D., director of the ALS Center of Excellence at U-M and James W. Albers Distinguished University Professor at U-M.

"These preclinical studies are the required first step on the road to stem cell therapies."

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Building More Homes for Hematopoietic Stem Cells

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A new study reveals how stem cell niche generation is regulated in bone marrow, which could lead to improvements in stem cell transplantation for the treatment of blood diseases.  

Bone marrow transplants give patients new blood stem cells to replace original diseased cells and have helped millions of people with blood disorders, including cancer. 

But for about one in every 10 patients, the introduced cells never take hold in the patient’s bone marrow, leaving patients open to severe infections and bleeding events that are often fatal.  

By uncovering the mechanism that creates stem cell niches in bone marrow, the new study from Columbia Stem Cell Initiative researchers could lead to ways to increase the number of niches before transplantation and improve overall engraftment of transplanted cells. 

“To improve engraftment, people have generally focused on improving the stem cells themselves, but these stem cells live in niches, specialized microenvironments in the bone marrow that nurture and protect the stem cells,” says Lei Ding, the Gurewitsch and Vidda Foundation Associate Professor of Microbiology & Immunology and Rehabilitation & Regenerative Medicine, who led the research. 

“If we can create more niches, even without changing anything else, we should be able to increase the number of transplanted cells that engraft in the bone marrow and reduce graft failure.” 

New niche generation requires m6a modifications

Little attention has been paid to how the niche is generated during development, because researchers had largely overlooked this process and considered the niche as a static, pre-existing structure. 

To identify mechanisms that control niche development, Ding’s team examined gene activity of mouse bone marrow cells during and after the creation of niches to look for genes upregulated only during niche creation.  

This analysis found that genes involved in mRNA processing and RNA methylation, particularly m6a modifications, were highly expressed during niche creation but not after.  

That led the researchers to the Mettl3 gene, which is responsible for adding m6a modifications to mRNA, and the discovery that Mettl3 activity is needed to generate stem cell niches. Without Mettl3, Ding’s team found, niche generation was compromised in both number and quality, more bone cells were generated, and fewer hematopoietic stem cells took up residence in the bone marrow.  

The researchers also identified a target of Mettl3—Klf2—which must be suppressed by m6a modifications during niche development. 

“This study is important because it reveals the first specific mechanism of niche creation,” Ding says, “and shows us that niche creation is controlled genetically.” 

“We are super excited about the possibility to create more niches by modulating gene function,” says first author Longfei Gao, a postdoctoral fellow in Ding’s lab. 

Artificial niches

The next step for the researchers is to see if they can increase niche generation in adult mice. 

 “At this stage we’re still doing a lot of genetics to find a driver that can boost niche creation, so we don’t yet have a way to translate our finding to patients,” Ding says. 

The findings may also be an important step toward the creation of niche organoids in the laboratory. 

“Right now, we can’t culture niche cells very well,” Ding says. “If we can create a niche in the lab, we can better understand how the niche supports stem cells and maybe use such systems to generate more stem cells for patient transplants.” 

Top image shows normal hematopoietic stem cell niches (pink) in the bone marrow of a mouse. Image provided by Lei Ding.

The research was supported by the National Institutes of Health (grants R01HL153487, R01HL155868, R01GM146061, and P30CA013696), a NYSTEM training grant, an American Heart Association postdoctoral fellowship, a Rita Allen Foundation Scholar Award, a Scholar Award from the Leukemia and Lymphoma Society, and an Irma Hirschl Research Award. 

All authors (from Columbia): Longfei Gao, Heather Lee, Joshua H. Goodman, and Lei Ding. 

The authors declare no competing interests. 

Office of the Vice President for Research

“human pluripotent stem cells twenty-five years on” webinar.

The discovery of human pluripotent stem cells just over twenty-five years ago almost immediately engendered widespread enthusiastic speculation concerning their future potential in research and medicine: a future as models for early human development, as platforms for functional human genomics, as tools for the study of disease, drug screening and toxicology, and as a renewable source of cellular therapeutics for a range of intractable diseases. In this lecture, Dr. Martin Pera, a noted expert in the pluripotent stem cell field, will assess the progress thus far and the prospects and challenge s ahead.

The UConn/UConn Health Stem Cell Research Oversight (SCRO) Committee invites you to this one-hour lecture followed by a 30-minute Q&A session! 

Date: Monday, May 13, 2024

Time:  4:00 p.m. – 5:30 p.m. EDT

Presenter:   Dr. Martin Pera

Topic:  Human Pluripotent Stem Cells Twenty-Five Years On

Registration Link:   WebEx Registration Link

Martin Pera, Ph.D., The Jackson Laboratory

Martin Pera is a Professor at the Jackson Laboratory in Bar Harbor, Maine. He is the Chair of the Steering Group of the International Stem Cell Initiative, a member of the Board of Directors of the International Society for Stem Cell Research, and Editor-in-Chief of the society’s journal, Stem Cell Reports. His laboratory when at Monash University was the second in the world to isolate embryonic stem cells from the human blastocyst, and the first to describe their differentiation into somatic cells (neurons) in vitro. His current research is focused on understanding cell state transitions in pluripotent stem cells, and on the use of pluripotent stem cells to study disorders of the central nervous system and the development of cell therapy for age-related macular degeneration. Dr. Pera’s research interests are the cell biology of pluripotency and the applications of human pluripotent stem cells in disease modeling and therapy. 

For questions, contact Ellen Ciesielski, UConn/UConn Health SCRO Coordinator, Research Integrity & Compliance.

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Yale Cancer Center Earns International Reaccreditation for Expertise in CAR T-cell Therapy and Stem Cell Transplantation

Ycc sch fact accredited.

Yale Cancer Center (YCC) and Smilow Cancer Hospital (SCH) have again received an internationally recognized accreditation for cellular therapy and stem cell transplantation.

Yale Cancer Center (YCC) and Smilow Cancer Hospital (SCH) have again received an internationally recognized accreditation for cellular therapy and stem cell transplantation from the Foundation for the Accreditation of Cellular Therapy (FACT) , giving patients lifesaving cancer treatment options in Connecticut. SCH is the only cancer hospital in the state offering these therapies, including chimeric antigen receptor (CAR) T-cell therapy. A new cellular therapy, tumor infiltrating lymphocyte (TIL) therapy , will be available soon for melanoma.

“FACT accreditation has evolved into a necessary qualification to be accepted and competitive in the field of cellular therapy,” said Stuart Seropian, MD , clinical director and lead physician of the stem cell transplant program at YCC and SCH. “This accreditation shows that we strive to achieve the highest quality care for cellular therapy treatment programs.”

YCC and SCH uphold the most rigorous standards in every aspect of transplantation and cellular therapy – from clinical care to donor management, cell collection, processing, storage, transportation, administration, and cell release. There are currently 310 FACT-accredited institutions worldwide.

What are cellular therapies?

SCH is one of a select group of hospitals and cancer centers that offer CAR T-cell therapy (a type of immune effector cell therapy) to patients with solid tumors, relapsed/refractory melanoma, and even disease areas beyond oncology.

CAR T-cell therapy is a relatively new and highly personalized type of immunotherapy drug that uses a patient’s synthetically modified T cells — a type of white blood cell — to kill cancer cells. Dr. Seropian said CAR T is “an exciting new form of immunotherapy that is proving effective in patients with certain recurrent or resistant blood cancers.”

YCC and SCH will soon offer (TIL) therapy cellular therapy for melanoma that was recently approved by the Food and Drug Administration. Doctors grow a large number of tumor infiltrating lymphocyte cells in the lab from a sample of a patient’s own tumor and return the cells to the body to seek out and combat tumors.

What is stem cell transplantation?

A stem cell transplant, which is also known as a bone marrow transplant, is a medical procedure in which healthy stem cells from a donor replace damaged or diseased bone marrow. The healthy stem cells can then develop into new, healthy bone marrow and blood cells. The procedure can be used to treat various cancers of the blood, bone marrow, or lymph system such as leukemia or lymphoma.

YCC physicians at SCH offer transplantation, using compatible donor stem cells, which is known as an allogeneic transplant or using a patient’s own stem cells, which is known as an autogulous transplant .

A leader in cellular therapy and stem cell transplant

The stem cell transplant program at YCC and Smilow first received FACT accreditation in 2003, and reaccreditation occurs every three years.

YCC and SCH are members of the National Marrow Donor Program. This program tracks data on patients who have received a transplant at accredited United States Transplant Centers. Data from the program shows that after one year, patients who receive a stem cell transplant at Smilow Cancer Hospital have a 9 percent higher expected one year survival rate than the national rate of 63%.

Smilow also ranks as a top hospital in U.S. News & World Report as one of the "America's Best Hospitals" for leukemia, lymphoma, and myeloma — three conditions for which ceullar therapy and stem cell transplants may be necessary.

To make an appointment with a Yale Cancer Center physician, click here .

About Yale Cancer Center and Smilow Cancer Hosptial

Yale Cancer Center combines a tradition of innovative cancer treatment and quality care for our patients. A National Cancer Institute (NCI) designated comprehensive cancer center since 1974, Yale Cancer Center is one of only 56 such centers in the nation and the only one in Connecticut. Yale Cancer Center members include national and internationally renowned scientists and physicians at Yale School of Medicine and Smilow Cancer Hospital. This partnership enables the Center to provide the best approaches for prevention, detection, diagnosis, and treatment for cancer.

Smilow Cancer Hospital at Yale New Haven Health is one of the nation’s pre-eminent cancer hospitals, Connecticut’s largest provider of cancer care, and the only comprehensive cancer facility in the Northeast – bringing together both inpatient and outpatient care in one hospital. In addition to the flagship Smilow Cancer Hospital in New Haven, Smilow offers state-of-the-art cancer services at 15 other locations throughout the region. Partnering with Yale Cancer Center, Smilow Cancer Hospital offers the very latest care, delivered by some of the nation’s most prominent and highly respected physicians and nurses. A leader in groundbreaking academic medicine, Smilow provides access to more than 300 clinical trials – bringing innovation and new hope to patients each year, including access to Phase I trials.

Featured in this article

• Stuart Seropian, MD Professor of Internal Medicine (Hematology); Acting Director, Stem Cell Transplantation; Chairman, Car-T Cell Joint Steering Committee; Director, Unrelated Donor Transplant Program, Stem Cell Transplantation; Co-Director, Immune Effector Cell Therapy; Co-Director, Adult CAR T-Cell Therapy Program

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First Patient Begins Newly Approved Sickle Cell Gene Therapy

A 12-year-old boy in the Washington, D.C., area faces months of procedures to remedy his disease. “I want to be cured,” he said.

By Gina Kolata

Photographs by Kenny Holston

Gina Kolata visited Kendric and his parents at the hospital in Washington, D.C., when he was having his stem cells extracted

On Wednesday, Kendric Cromer, a 12-year-old boy from a suburb of Washington, became the first person in the world with sickle cell disease to begin a commercially approved gene therapy that may cure the condition.

For the estimated 20,000 people with sickle cell in the United States who qualify for the treatment, the start of Kendric’s monthslong medical journey may offer hope. But it also signals the difficulties patients face as they seek a pair of new sickle cell treatments.

For a lucky few, like Kendric, the treatment could make possible lives they have longed for. A solemn and shy adolescent, he had learned that ordinary activities — riding a bike, going outside on a cold day, playing soccer — could bring on episodes of searing pain.

“Sickle cell always steals my dreams and interrupts all the things I want to do,” he said. Now he feels as if he has a chance for a normal life.

Near the end of last year, the Food and Drug Administration gave two companies authorization to sell gene therapy to people with sickle cell disease — a genetic disorder of red blood cells that causes debilitating pain and other medical problems. An estimated 100,000 people in the United States have sickle cell, most of them Black. People are born with the disease when they inherit the mutated gene for the condition from each parent.

The treatment helped patients in clinical trials , but Kendric is the first commercial patient for Bluebird Bio, a Somerville, Mass., company. Another company, Vertex Pharmaceuticals of Boston, declined to say if it had started treatment for any patients with its approved CRISPR gene-editing-based remedy .

Kendric — whose family’s health insurance agreed to cover the procedure — began his treatment at Children’s National Hospital in Washington. Wednesday’s treatment was only the first step. Doctors removed his bone marrow stem cells, which Bluebird will then genetically modify in a specialized lab for his treatment.

That will take months. But before it begins, Bluebird needs hundreds of millions of stem cells from Kendric, and if the first collection — taking six to eight hours — is not sufficient, the company will try once or twice more.

If it still doesn’t have enough, Kendric will have to spend another month in preparation for another stem cell extraction.

The whole process is so involved and time-consuming that Bluebird estimates it can treat the cells of only 85 to 105 patients each year — and that includes not just sickle cell patients, but also patients with a much rarer disease — beta thalassemia — who can receive a similar gene therapy.

Medical centers also have the capacity to handle only a limited number of gene therapy patients. Each person needs expert and intensive care. After a patient’s stem cells have been treated, the patient has to stay in the hospital for a month. For most of that time, patients are severely ill from powerful chemotherapy.

Children’s National can accept only about 10 gene therapy patients a year.

“This is a big effort,” said Dr. David Jacobsohn, chief of the medical center’s division of blood and marrow transplantation.

Top of the Waiting List

Last week, Kendric came prepared for the stem cell collection — he has spent many weeks in this hospital being treated for pain so severe that on his last visit, even morphine and oxycodone could not control it. He brought his special pillow with a Snoopy pillowcase that his grandmother gave him and his special Spider-Man blanket. And he had a goal.

“I want to be cured,” he said.

Bone marrow stem cells, the source of all the body’s red and white blood cells, are normally nestled in a person’s bone marrow. But Kendric’s doctors infused him with a drug, plerixafor, which pried them loose and let them float in his circulatory system.

To isolate the stem cells, staff members at the hospital inserted a catheter into a vein in Kendric’s chest and attached it to an apheresis machine, a boxlike device next to his hospital bed. It spins blood, separating it into layers — a plasma layer, a red cell layer and a stem cell layer.

Once enough stem cells have been gathered, they will be sent to Bluebird’s lab in Allendale, N.J., where technicians will add a healthy hemoglobin gene to correct the mutated ones that are causing his sickle cell disease.

They will send the modified cells back three months later. The goal is to give Kendric red blood cells that will not turn into fragile crescent shapes and get caught in his blood vessels and organs.

Although it takes just a couple of days to add a new gene to stem cells, it takes weeks to complete tests for purity, potency and safety. Technicians have to grow the cells in the lab before doing these tests.

Bluebird lists a price of $3.1 million for its gene therapy, called Lyfgenia. It’s one of the highest prices ever for a treatment.

Despite the astronomical price and the grueling process , medical centers have waiting lists of patients hoping for relief from a disease that can cause strokes, organ damage, bone damage, episodes of agonizing pain and shortened lives.

At Children’s National, Dr. Jacobsohn said at least 20 patients were eligible and interested. The choice of who would go first came down to who was sickest, and whose insurance came through.

Kendric qualified on both counts. But even though his insurance was quick to approve the treatment, the insurance payments are only part of what it will cost his family.

Chances and Hopes

Deborah Cromer, a realtor, and her husband, Keith, who works in law enforcement for the federal government, had no idea they might have a child with sickle cell.

They found out only when Deborah was pregnant with Kendric. Tests showed that their baby would have a one-in-four chance of inheriting the mutated gene from each parent and having sickle cell disease. They could terminate the pregnancy or take a chance.

They decided to take a chance.

The news that Kendric had sickle cell was devastating.

He had his first crisis when he was 3. Sickled blood cells had become trapped in his legs and feet. Their baby was inconsolable, in such pain that Deborah couldn’t even touch him.

She and Keith took him to Children’s National.

“Little did we know that that was our introduction to many many E.R. visits,” Deborah said.

The pain crises became more and more severe. It seemed as though anything could set them off — 10 minutes of playing volleyball, a dip in a swimming pool. And when they occurred, Kendric sometimes needed five days to a week of treatment in the hospital to control his pain.

His parents always stayed with him. Deborah slept on a narrow bench in the hospital room. Keith slept in a chair.

“We’d never dream of leaving him,” Deborah said.

Eventually the disease began wreaking severe damage. Kendric developed avascular necrosis in his hips — bone death that occurs when bone is deprived of blood. The condition spread to his back and shoulders. He began taking a large daily dose of gabapentin, a medicine for nerve pain.

His pain never let up. One day he said to Deborah, “Mommy, I’m in pain every single day.”

Kendric wants to be like other kids, but fear of pain crises has held him back. He became increasingly sedentary, spending his days on his iPad, watching anime or building elaborate Lego structures.

Despite his many absences, Kendric kept up in school, maintaining an A average.

Deborah and Keith began to hope for gene therapy. But when they found out what it would cost, they lost some of their hope.

But their insurer approved the treatment in a few weeks, they said.

Now it has begun.

“We always prayed this day would come,” Deborah said. But, she added, “We’re nervous reading through the consents and what he will have to go through.”

Kendric, though, is looking forward to the future. He wants to be a geneticist.

And, he said, “I want to play basketball.”

An earlier version of this article misstated the location of a lab. It is in Allendale, N.J., not Allentown.

How we handle corrections

Gina Kolata reports on diseases and treatments, how treatments are discovered and tested, and how they affect people. More about Gina Kolata

Kenny Holston is a Times photographer based in Washington, primarily covering Congress, the military and the White House. More about Kenny Holston

News and views for the UB community

• Stories >

Root canal? Next-gen treatment could involve stem cells, not surgery

research news

UB faculty member Camila Sabatini’s research investigating novel biologically based avenues for tooth repair may reduce the need for root canals, a procedure in which the nerve of an infected tooth is removed and the canals are sealed with synthetic material.

By LAURIE KAISER

Published May 7, 2024

Camila Sabatini, associate professor of restorative dentistry in the School of Dental Medicine, has received the Harold Amos Medical Faculty Development Program (AMFDP) award from the Robert Wood Johnson Foundation to study novel therapies to repair damaged teeth.

The selective four-year, $420,000 grant will allow Sabatini to investigate strategies for the regeneration of tooth defects. She will work in collaboration with Techung Lee, associate professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences. Frank Scannapieco, SUNY Distinguished Professor of Oral Biology, will serve as adviser in this fellowship.

The award, traditionally reserved for promising physician-scientists to help them advance toward achieving a senior rank in academic medicine, expanded in scope to include dentistry in 2012 and nursing in 2015.

“As the only dentist in a cohort of 16 scholars selected this year, this award reflects her outstanding contributions to the field,” Scannapieco says.

Sabatini’s research investigating novel biologically based avenues for tooth repair may reduce the need for root canals and could potentially have major implications in the way dental care is rendered.

“Root canals happen when an infection has advanced to the nerve of the tooth,” Sabatini explains. “The nerve is removed, and the canals are sealed with a synthetic material. The loss of vitality weakens the tooth, making it prone to fracture.”

In this proposal, Sabatini says, the team will investigate ways to use stem cells of dental origin to promote the repair of damaged teeth, potentially avoiding the need for a root canal.

 “Over the past two decades, scientists have come to rely on stem cells for tissue regeneration. We haven’t tapped into that nearly enough in dental medicine,” Sabatini notes. “The standard of care in dentistry today — fillings and implants — is still quite outdated, as it is based on the use of synthetic materials only. We are looking to increase our understanding of the biology of the host, so we can identify potential avenues for tissue repair.”

Cancer therapy drugs and gene therapy

The four-year grant will allow the team to investigate a drug-repurposing approach with an immunostimulant drug used in cancer therapy and a gene therapy strategy.

“The appeal of drug repurposing is the potential for immediate clinical translation, since phase I trials can be bypassed, moving directly to phase II trials,” Sabatini says. “Gene therapy could provide a cost-effective avenue for the healing of tooth defects.”

The therapies will be investigated using dental pulp stem cells obtained from extracted human molars and animal trials in mice, where artificially induced tooth defects will receive the various therapies. The animal studies proposed under this award could take the investigators a step closer to the next phase in the process of regulatory approvals of therapies and devices by the Food and Drug Administration (FDA).

“The possible impact of this research is profound,” Scannapieco says. “These innovative technologies have the potential to be widely applicable and cost-effective, ushering in a significant paradigm shift in dental care.” 

Advancing team science, research-driven dental education

Sabatini joined the dental school in 2007 as a clinical assistant professor and was promoted to associate professor in 2015. She also currently serves as an adjunct professor of oral biology and of chemical and biological engineering.

A previous recipient of a National Institutes of Health (NIH) research award — in collaboration with Chong Cheng, professor, and Mark Swihart, SUNY Distinguished Professor and chair, both of the Department of Chemical and Biological Engineering — Sabatini has worked toward advancing a vision of team science and research-driven dental education.

“Embracing science at the core of dental education is the only path forward,” she says. “We, in academic centers, have a monumental task to evolve in our understanding of the profession and the factors that will influence the future workforce supply and demand.

“Understanding changes happening in dental practice will guide academic centers in meeting these demands. Several therapies will make their way into the profession over the next decade. Regenerative dentistry, while still in the early stages, will make its way into the mainstream as a non-invasive treatment option.”

Sabatini’s AMFDP award followed a competitive peer-reviewed process with members of a national advisory committee affiliated with such agencies as the American Heart Association and the National Institute of Diabetes and Digestive and Kidney Diseases, among others.

“I am thrilled about this opportunity,” Sabatini says. “I look forward to continuing to build my research program, expanding into the field of regenerative medicine and contributing to the NIH-funded pool of dentist/scientists for the advancement of this work.”

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• Published: 14 February 2023

Progress and challenges in stem cell biology

• Effie Apostolou 1 ,
• Helen Blau 2 ,
• Kenneth Chien 3 ,
• Madeline A. Lancaster 4 ,
• Purushothama Rao Tata 5 ,
• Eirini Trompouki 6 ,
• Fiona M. Watt 7 ,
• Yi Arial Zeng 8 , 9 &
• Magdalena Zernicka-Goetz 10 , 11  

Nature Cell Biology volume  25 ,  pages 203–206 ( 2023 ) Cite this article

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Since stem cells were first discovered, researchers have identified distinct stem cell populations in different organs and with various functions, converging on the unique abilities of self-renewal and differentiation toward diverse cell types. These abilities make stem cells an incredibly promising tool in therapeutics and have turned stem cell biology into a fast-evolving field. Here, stem cell biologists express their view on the most striking advances and current challenges in their field.

Effie Apostolou: induced pluripotency — the continued reprogramming revolution

The seminal discovery of pluripotency induction achieved by means of transcription factors or chemical cocktails has revolutionized multiple biomedical fields and shed light on processes including development, aging, regeneration and cancer. Over the past 15 years, many burning questions around reprogramming mechanisms, trajectories and translational limitations have been addressed.

High-throughput functional screens identified critical regulators and barriers of reprogramming, while multimodal omics studies helped with constructing four-dimensional (4D) roadmaps of the complex transcriptional, epigenetic, topological, proteomic and metabolic changes that somatic cells undergo upon loss of their initial identity and acquisition of pluripotency. Parallel studies have also identified potentially detrimental, long-lasting aberrations that are introduced along the way. Moreover, single-cell technologies during cellular reprogramming captured intriguing intermediate and refractory states, reminiscent of early embryonic fates, senescence response, regeneration or tumorigenesis.

Despite this progress, important gaps remain and new questions continually arise. What are the cause-and-effect relationships during the multi-layered molecular chain reaction of reprogramming, and which factors lie at the top of the regulatory hierarchy? How can we reproducibly and deterministically reprogram cell identity, if we know the start and end points, to enable efficient and safe generation of any therapeutically relevant cell type from easily accessible tissues? How can we either avoid or rationally exploit the epigenetic variability of induced pluripotent stem cells? Can we capture, and propagate in vitro, transient intermediate cell states of biomedical relevance? Future studies using advanced engineering approaches for acute and reversible perturbations in defined time windows will be critical to address the functional interconnections of various reprogramming regulators and enable fine-tuning toward end states of interest. Moreover, ongoing single-cell efforts to map the continuum of cell states in early embryos and tissues or synthetic structures will determine more definitively the degree to which reprogramming intermediates recapitulate physiological or pathological transitions. Together with continuously improved computational approaches and modelling, these efforts will enable accurate predictions of critical conditions and cocktails for precise, reproducible and error-free cell fate engineering. These engineered fates can ultimately expand the toolbox for generating complex tissues and organoids for disease modelling and drug screening and for understanding and ameliorating hallmarks of ageing and cancer.

Helen Blau: multiple strategies to augment muscle regeneration and increase strength

Mobility is a major determinant of quality of life. Elderly patients with sarcopenia or patients with heritable muscle-wasting disorders suffer from a debilitating loss of muscle strength for which there is no approved treatment. COVID-19 highlighted the need for strategies to strengthen atrophied diaphragm muscles after ventilator support. Although our knowledge of stem cell function in regeneration has markedly increased, major knowledge gaps and challenges remain.

First, muscle stem cells (MuSCs) are a heterogeneous population that diverges over time and in response to disease or ageing. Targeting the functional subset of MuSCs is an unmet challenge. Second, understanding the role of the microenvironment and the muscle stem cell niche in muscle stem cell behaviour is key. Data are emerging showing that MuSCs respond not only to biochemical but also to biomechanical cues and that the elasticity of the niche matters. This suggests that stiffer fibrotic muscles, characteristic of muscular dystrophy or ageing, will harbour stem cells with impaired regenerative function. The development of hydrogels that can stiffen or soften on demand, while maintaining stem cells in a viable state, could provide new molecular and signalling insights into stem cell mechanosensing mechanisms, how they change with ageing and how they can be overcome. Third, from advances in single-cell and single-nuclei RNA sequencing, we are gaining knowledge of the gene expression patterns of the complex, diverse array of cell types that populate the niche. However, these technologies entail tissue destruction and therefore do not provide spatial information regarding cell–cell interactions that are crucial to maintaining stem cell quiescence and inducing stem cell activation and efficacious regeneration. There is a great need for spatial proteomics and multiplexed imaging modalities that preserve information about cell location and the dynamics of cell–cell interactions characteristic of regeneration, disease and ageing. Finally, inflammation has beneficial roles in wound healing, but is deleterious when chronic, as in aged muscles. Finding ways to rejuvenate muscle form and function remains a major challenge. The discovery of the prostaglandin degrading enzyme 15-PGDH, an immune modulator, as a pivotal molecular determinant of muscle ageing is a notable step in that direction. Remarkably, overexpression of 15-PGDH for one month in young adult mouse muscles induces atrophy and weakness, whereas inhibition of 15-PGDH in aged mouse muscles results in a 15% increase in muscle mass, strength and exercise performance. Solving these challenges will pave the way for new, effective stem cell-targeted therapeutic agents to regenerate and rejuvenate muscle.

Kenneth Chien: heart progenitors rebuild cardiac muscle

Rebuilding the failing human heart with working muscle is the holy grail of regenerative medicine. Although initial therapeutic attempts with non-cardiac cells have proven unfruitful, mouse studies have shown the potential to create de novo cardiomyocyte-like cells in situ by direct reprogramming via gene transfer. A novel class of adult claudin-6 + epicardial progenitors can convert to muscle, contributing to regeneration of the injured vertebrate heart. The studies point to a key role of tight junction proteins in the formation of a honeycomb-like regenerative structure. Although the adult human epicardium lacks these specific progenitors, uncovering their regenerative molecular pathways could identify new signals that can restore the myogenic potential of non-human epicardial cells via conversion to a progenitor state.

Thus far, the most advanced stem cell therapeutic agents are based on human embryonic stem (ES) cells for the generation of either cardiomyocytes or human ventricular progenitors (HVPs) for transplantation in large animals following cardiac injury. Issues of scalability, efficacy, clear evidence of working ventricular muscle grafts, lack of teratoma formation and tissue integration have all been largely addressed, moving both ES-cell-derived cell types toward the clinic with large pharma partners. However, additional issues remain, including safety (arrhythmias), durability (rejection) and the development of clinically tractable in vivo delivery systems. Our work on cardiogenesis over two decades recently led to the discovery of HVPs, which can migrate toward the injury site, prevent fibrosis via fibroblast repulsion, and proliferate to form large human ventricular muscle grafts to improve function in failing pig hearts. Additional work is ongoing, but early returns support the therapeutic potential of HVPs with minimal major side effects, with a two-year projected timeline for a first-time-in-human study. Prevention of rejection with optimal drug regimens, hypoimmune ES cell lines and new tolerization strategies, as well as novel catheters for in vivo delivery, are on the horizon. With these advances, HVPs might eventually provide new hope for patients with near-end-stage heart failure and no other options.

Madeline A. Lancaster: next-generation human neural stem cell models

The field of neural stem cell biology has made great strides in the past decade. What started out with neural stem cells that were cultured ex vivo to generate neurons and glia has evolved into a diverse field of ever-more-complex tools to model not just individual cells, but whole 3D neural tissues in a dish called neural organoids. Such organoids mimic not only the cellular makeup of the developing brain, but also local tissue architecture, with recent methods even demonstrating morphogenetic movements of neurulation.

Organoids and other in vitro models of the nervous system are becoming increasingly complex, for example through the use of so-called assembloids to combine different regions and examine their integration. Neural organoids also enable extensive neuronal maturation, even reaching hallmarks seen in the postnatal brain. However, as these models increase in complexity, so too do the challenges. With increasing size and maturity, the lack of vasculature becomes problematic. Although promising results have come from in vivo transplantation and integration of endothelial cells, vascularization leading to more advanced tissue development remains to be demonstrated. This challenge will likely represent one of the most difficult hurdles not just for the neural organoid community, but for the field of organoids as a whole, and creative approaches will be needed.

Brain organoids are already paving the way to fundamental discoveries in human neurobiology and are providing new understanding of disease pathogenesis. The future will hold new insight into why the human brain is unique, as well as how to prevent and treat various neurological conditions. Organoids may hold the key to these insights, but they cannot be the only tool, and it will be important to use them as complementary approaches alongside more established methods. Marrying in vitro and in vivo approaches will be the key to uncovering fundamental processes of neurobiology and answer age-old questions such as how genetics influence connectivity, how networks of neurons compute and how information is stored in the brain. The brain is still a largely uncharted territory, and powerful techniques combined with creative minds are needed to untangle its mysteries.

Purushothama Rao Tata: phenotypic and functional interrogation of lung biology at single-cell resolution

Lung tissues are relatively quiescent at homeostasis, but they respond rapidly to regenerate lost cells after injury. Early lineage tracing studies in animal models showed that this regeneration is driven predominantly by several ‘professional’ and facultative stem and progenitor cells in different regions of the lung, including basal and secretory cells in the airways and type 2 pneumocytes in the alveoli. These studies also uncovered a remarkable plasticity of some differentiated cell populations that contribute to regeneration following severe injury. More recently, multiple groups have used single-cell omics approaches to catalogue lung cells and their associated molecular signatures in great detail. Remarkably, in the case of the human lung, these efforts have identified previously unknown and uncharacterized cell types located in discrete regions. These cell populations are often quite heterogeneous, and include transitory states enriched in lungs from patients with respiratory disease. Significantly, these cell types are not found in the mouse, the animal model most commonly used for lung research. Consequently, there is an urgent need to develop new experimental tools to test their normal in vivo function and role in regeneration and disease.

To address this problem, efforts are underway by several groups, including our own, to develop genetically engineered ferrets and pigs as new animal models. Similarly, analytical tools are being optimized to infer cell lineages in human lungs based on clonally amplified genetic variants (single-nucleotide polymorphisms or mitochondrial heteroplasmy). In the case of ex vivo organotypic cultures, such as those derived from human induced pluripotent stem cells or primary foetal or adult lung progenitors, there remain many challenges. These include attaining or retaining mature cell types in the correct ratios to match those in normal in vivo lung tissue. To overcome this challenge, collaborative efforts are underway between lung stem cell biologists and bioengineers to generate new scaffolds to reassemble and mimic the cell–cell interactions found in native lung tissue niches. Taken together, these new approaches have the potential to identify the genetic circuits that regulate normal and disease-associated human lung cell states, establish scalable disease models and, ultimately, develop cell-based therapies to treat degenerative lung diseases.

Eirini Trompouki: the time journey of blood stem cells

Haematopoietic stem and progenitor cells (HSPCs) are critical for sustaining lifelong haematopoiesis via their extensive self-renewal and multilineage differentiation capacities. The secrets to how HSPCs acquire these capacities reside in the enigmatic process through which they are generated during an embryonic endothelial-to-haematopoietic transition (EHT). On the other end of the spectrum, age alters HSPCs, resulting in defective haematopoiesis. The most critical problems in HSPC biology relate to these lifetime bookends. Recently, human HSPC development was addressed in a spatial and single-cell manner, revealing that a haematopoietic stem cell (HSC) transcriptional signature is established after the emergence of HSCs along with continuously evolving cell surface markers, while haematopoietic heterogeneity already starts to be established at the haemogenic endothelium stage. Single-cell transcriptomics also led to the identification of a progenitor population that is responsive to retinoic acid and gives rise to haemogenic endothelial cells. Our group and others pinpointed the importance of DNA and RNA sensors in EHT. We and others found that transposable elements and R-loops trigger innate immune sensors to induce sterile inflammation that enhances EHT. Another layer of regulation lies in the interaction between HPSCs and other cells, such as macrophages or T cells, that are proposed to perform quality control of HSPCs during development and adulthood, respectively. Despite this progress, however, we still cannot faithfully recapitulate EHT in vitro and produce the massive quantities of HPSCs required for transplantations and gene therapy. Therefore, I think one of the most important aspects of haematology in the near future will be generating and maintaining good quality and quantity of HSPCs in vitro.

Ageing of HSPCs, on the other hand, is especially relevant because the population of the Earth is continuously ageing. An interesting feature of ageing that is lately gaining more and more attention is clonal haematopoiesis, which has been linked to haematological (and other) diseases. Inflammation, chemotherapy and irradiation have been shown by many groups to be advantageous for mutated clones. It is interesting to speculate that a collection of stressful moments experienced during life are ‘memorized’ by HSPCs and aided by clonality to instigate ageing. It was recently demonstrated that epigenetic memory is a feature not only of immune cells but also of HSCs. Further research needs to show whether every stress in life could be depicted in our genome as ‘memory’ and finally constitute the intricate mechanism of ageing.

Fiona M. Watt: understanding epidermal stem cell biology through data integration

Although mammalian skin contains many different cell types, the best-characterized stem cell population is in the epidermis, the multilayered epithelium that forms the skin surface. Autologous sheets of cultured epidermis were one of the first cell therapies involving ex vivo expansion of stem cells to be validated clinically, dating back to the early 1980s. That approach has been refined over the years, and the life-saving effects of combining cell and gene therapy to treat blistering skin disorders have been demonstrated unequivocally. In parallel with the development of techniques to culture human epidermis, the mouse became a key model for stem cell studies because of the availability of tools to target the different epidermal layers and the demonstration that genetic lesions in humans could be phenocopied in the mouse. With the advent of extensive single-cell RNA sequencing (scRNA-seq) databases for healthy and diseased human skin, it is essential that stem cell researchers use these resources both to validate their experimental models and to design new experiments. We need to look hard at the extent to which mouse models are still appropriate for modelling healthy and diseased human skin.

A very exciting challenge we face is data integration. There are many different axes along which integration can be achieved. One is spatiotemporal — the ability to correlate changes in cell types and states as a function of time and distribution within the skin. I am particularly intrigued by the possibility of correlating macroscopic skin features that are captured by optical coherence tomography with features obtained via spatial transcriptomics. Another example is integrating epidermal datasets from transcriptomics, proteomics, lipidomics and glycomics to gain a more holistic understanding of the nature of the stem cell state. In our enthusiasm for scRNA-seq, we risk ignoring the central dogma that DNA makes RNA that makes protein, and failing to remember the importance of protein modifications and turnover. I believe that by integrating epidermal stem cell responses to different extracellular cues, whether physical or biochemical, we will gain new insights into stem cell function and find switches between cell states that are conserved between tissues.

Yi Arial Zeng: the journey to islet regeneration

The islets of Langerhans are endocrine regions of the pancreas containing hormone-producing cells. β-cells produce and secrete insulin — the hormone that lowers blood glucose levels. Insufficient numbers of functional β-cells are associated with both type 1 and late-stage type 2 diabetes. With 1 in 11 people being diabetic, there is a great need to understand how the adult islet mass is maintained and how β-cells are regenerated to guide new therapies.

Stimulation of in situ islet regeneration is one approach for replenishing β-cells, through the formation of new progenitor-derived β-cells and enhanced proliferation of existing β-cells. Although the existence of islet progenitors in postnatal life has long been debated, recent work using mouse models has reported their existence in adults, leading to exciting opportunities for dissecting the activation mechanisms of these progenitors during homeostasis, regeneration and aging. It is noteworthy that neogenesis from progenitors and β-cell replication are not mutually exclusive: the proliferative β-cell subpopulation could possibly be the progeny of the progenitors, or there could be parallel proliferative pathways. Considering that relatively few insulin-secreting cells are needed to ameliorate hyperglycaemia, in vivo transdifferentiation represents another promising route. It has been reported that pancreatic exocrine cells and gut cells can be transdifferentiated into insulin-secreting cells. Collectively, these approaches aim to offer therapeutic strategies to stimulate in situ regeneration.

Pancreatic islet transplantation from donors is a recognized approach for replacing lost or damaged β-cells. Because of the shortage of donors, ongoing efforts aim to identify a renewable supply of human β-cells. A promising idea involves the differentiation of human pluripotent stem cells into β-like cells, and clinical trials using these β-like cells are underway. However, one may ask whether transplanting only mature β-cells is optimal, as proper glucose regulation requires coordination between various islet cell types. Will it be advantageous to produce whole islets in vitro rather than differentiating cells solely into β-like cells? Murine adult islet progenitors can generate organoids that contain all endocrine cell types of the intact islet and are proven to ameliorate diabetes in murine models. More work will be needed to establish the identity of these progenitors in the human pancreas and to translate the organoid culture system to human cells. As our understanding of islet regeneration matures, therapeutic transplant options will continue to emerge.

Magdalena Zernicka-Goetz: stem cells in modelling embryology

ES cells, derived from the pluripotent epiblast, can host transgenes and be reintroduced back into the embryo to generate a chimeric animal and a pure breeding line in future generations. A stunning application of ES cells in recent years has been their use to generate embryo-like structures in vitro. Several approaches have advanced our quest to recapitulate embryogenesis.

A 2D method using exclusively ES cells cultured as micropatterns offered a powerful route toward understanding how different cell types are established and signal between themselves. A second model, in which large aggregates of ES cells are treated with chemicals and growth factors, generated 3D structures developing many aspects of the segmental body plan, although still lacking body regions, particularly those required for forebrain development.

The importance of extraembryonic signalling was recognized through a series of whole-embryo models. The first such model, built from ES cells alone, pointed to the role of signals normally provided by the extraembryonic primitive endoderm, which can be replaced by the extracellular matrix to polarize ES cells to form a rosette-like structure that undertakes lumenogenesis. The second model, built from ES cells and trophectoderm stem cells, taught us that this interaction alone is sufficient to establish amniotic cavity and posterior embryo identity to induce mesoderm and germ cells. By incorporating a third stem cell type, extraembryonic endoderm cells, we achieved the formation of the anterior signalling centre and anterior–posterior patterning. Recently, additional approaches we and others undertook led to the generation of embryo models that were capable of developing much further to establish brain and heart structures and initiate organogenesis. Such whole-embryo-like models have brought insight into the biophysical and biochemical factors mediating stem cell self-organization and defining the cellular constituents, the chemical environment and the physical context required for embryo assembly.

Despite this progress, challenges remain. Cell fate specification relies on chemical cross-talk within and between lineages. Cell fate decisions must be spatiotemporally coordinated by establishing and interpreting gradients of numerous diffusible signalling proteins. We have much to learn about these combinatorial effects and about how to improve the efficiency with which different cell types combine to form embryo-like structures. A deep understanding of the components of cellular, biochemical and biophysical networks will be crucial to reaching this goal. Computational modelling will allow us to predict and guide self-organizational outcomes through exploitation of the capacity of cell communication to promote self-organization in vivo. It would also be powerful to advance our abilities to culture model embryos and replicate the maternal environment by delivering suitable nutrients to the circulatory system of the developing structure. These problems are also inherent to the assembly of synthetic organs, and I am certain that we will see a cross-talk between these different disciplines of synthetic biology for mutual benefit.

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Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

Effie Apostolou

Donald E. and Delia B. Baxter Foundation Professor for Stem Cell Biology, Stanford University School of Medicine, Stanford, CA, USA

Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

Kenneth Chien

MRC Laboratory of Molecular Biology, Cambridge, UK

Madeline A. Lancaster

Department of Cell Biology and Duke Regeneration Center, Duke University School of Medicine, Durham, NC, USA

Purushothama Rao Tata

IRCAN Institute for Research on Cancer and Aging, INSERM Unité 1081, CNRS UMR 7284, Université Côte d’Azur, Nice, France

Eirini Trompouki

Directors’ Research Unit, European Molecular Biology Laboratory, Heidelberg, Germany

Fiona M. Watt

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

Yi Arial Zeng

School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

Mammalian Embryo and Stem Cell Group, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

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Stem Cells Self-Organization Group, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

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• Published: 15 March 2010

Welcome to Stem Cell Research & Therapy

• Ann Donnelly 1 ,
• Surayya Johar 1 ,
• Timothy O'Brien 2 &
• Rocky S Tuan 3  

Stem Cell Research & Therapy volume  1 , Article number:  1 ( 2010 ) Cite this article

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Welcome to the first issue of the international open access journal Stem Cell Research & therapy , edited by Professor Rocky Tuan, of the University of Pittsburgh, and Professor Timothy O'Brien, of the National University of Ireland, Galway.

Stem Cell Research & Therapy aims to be the major forum for translational research into stem cell therapies. The journal has a special emphasis on basic, translational, and clinical research into stem cell therapeutics, including animal models, and clinical trials.

Stem cell research for therapeutic purposes has largely used adult stem cell sources. Embryonic stem cell research has enormous potential and also has major hurdles to overcome, not the least of which are ethical in nature. Funding for research into embryonic stem cells has also been in a state of transition. The change in US policy and subsequent National Institutes of Health guidelines allowing funding for human embryonic research has moved the use of stem cells of embryonic origin back into the spotlight [ 1 ]. Although legislation throughout the world varies, the international research community is striving to disseminate critical knowledge and useful ideas to aid the progress of our expertise in this area, and our open access policy will promote this.

Why is stem cell research important?

Stem cell research has great potential in the treatment of as-of-yet incurable diseases, including Huntington disease and Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. Other, more chronic conditions such as congestive cardiac failure, diabetes, and osteoarthritis may also respond well to stem cell therapy.

With the knowledge that stem cells can be induced to differentiate into specialized cells and that they can influence the tissues around them, the potential of stem cells as a therapeutic option is great. Recent advances have demonstrated that adult somatic cells, called induced pluripotent stem cells, can be reprogrammed into becoming stem-like in their nature and behavior [ 2 ].

Research is currently focused on calibration of the process of cell reprogramming, ensuring the quality of induced pluripotent stem cells, and modification of the stem cell niche. Future research will increasingly consider quality control of stem cell manufacture, delivery to the target areas, and architectural aids to ensure optimum placement and exposure of the stem cells.

Another important aspect of stem cell therapeutics will be a focus on the bioengineering of materials necessary to deliver and support stem cells on their therapeutic journey. Combinations of stem cell therapy with gene therapy will also expand the therapeutic repertoire as the effectiveness of the stem cell product may be enhanced via genetic modification. Thus, combinations of stem cells, biomaterials, and gene therapy may augment the therapeutic outcome but will result in complex regulatory challenges.

The potential paracrine mode of the therapeutic action of stem cells is worthy of substantial attention. Understanding the mechanism whereby stem cells heal tissue by regulating and interacting with host cells may lead to the development of novel therapeutic paradigms that may not require the stem cell per se as the therapeutic agent.

How and what will we publish?

BioMed Central is launching Stem Cell Research & Therapy to provide a new forum to highlight the growing area of stem cell therapeutics. In this open access journal, our research content will be made freely available upon publication. This means that readers worldwide will have immediate and free access to original research, promoting the immediate and wide distribution of the most current developments in the field [ 3 ]. Under our open access license, authors retain copyright of their article, allowing them, and any third party, to re-use their work as long as the authors are given correct attribution [ 4 ]. To cover the costs of open access, authors of original research are asked to pay an article-processing charge once their article has been accepted for publication. This is a flat fee that includes the use of color figures, unlimited pages, and additional data sets. Indeed, authors can upload both audio and visual files alongside their manuscript at no extra cost. To ensure permanence and high visibility, research published in Stem Cell Research & therapy will also be deposited in several international bibliographic databases [ 5 ].

Stem Cell Research & Therapy will publish original research as well as regular commissioned articles. Our reviews will provide a comprehensive overview of specific topics, collating and discussing the ever-changing advances in the field. There will be a specific focus on the therapeutic elements of stem cell research. Commentaries and viewpoint articles will be speculative and allow authors to be more opinionated in their views. Readers are firmly encouraged to participate and can do so by submitting letters to the editor on articles published in Stem Cell Research & therapy and on any issue in a related area. Brief comments can also be posted online on any article by using the tools displayed on the article's webpage. These tools will also allow articles to be shared via 'social media' services such as Facebook and Twitter, reflecting the commitment of the journal to disseminating our articles widely via the most popular and modern means.

We welcome your contributions

Stem Cell Research & Therapy will provide a platform for translational research into stem cell therapy. We are delighted to introduce this much-needed journal to the stem cell research community, and we welcome your responses and submissions. The Editors-in-Chief, supported by a global Editorial Board [ 6 ], are committed to making this journal a success, and we look forward to receiving your contributions.

National Institutes of Health Guidelines on Human Stem Cell Research. [ http://stemcells.nih.gov/policy/2009guidelines.htm ]

Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006, 126: 663-676. 10.1016/j.cell.2006.07.024.

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Ann Donnelly & Surayya Johar

REMEDI - National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland

Timothy O'Brien

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Rocky S Tuan

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AD and SJ are employees of BioMed Central and receive fixed salaries. TO and RT are the Editors-in-Chief of Stem Cell Research & Therapy and receive an annual honorarium.

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Donnelly, A., Johar, S., O'Brien, T. et al. Welcome to Stem Cell Research & Therapy . Stem Cell Res Ther 1 , 1 (2010). https://doi.org/10.1186/scrt1

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Assessing Immunogenicity of Products for Gene Therapy and T cell Therapy

Nirjal Bhattarai, Ph.D.

Office of Tissues and Advanced Therapies Division of Cellular and Gene Therapies Gene Transfer and Immunogenicity Branch

[email protected]

Dr. Bhattarai earned his PhD in Molecular and Cellular Biology from the University of Iowa Carver College of Medicine. He completed his postdoctoral training in the Division of Infectious Diseases at the University of Iowa Hospitals and Clinics. Early in his career, Dr. Bhattarai discovered a novel mechanism used by a non-pathogenic human RNA virus (GB virus C, formerly known as hepatitis G virus) to evade host immune responses and establish viral persistence. Additional studies disclosed that similar mechanisms are commonly used by related RNA viruses to evade host immune responses; however, the molecular mechanisms differ among viruses. His studies also disclosed novel mechanisms by which hepatitis C virus (HCV) and Yellow Fever virus (YFV) evade host immune responses.

Currently, his lab studies how RNA viruses of the Flaviviridae family evade host immune responses and use this knowledge to develop novel immunomodulatory gene therapy vectors with lower immunogenicity profiles.  His lab also studies inflammatory toxicities associated with engineered T cell therapy, such as CAR-T cells, in order to better understand mechanisms contributing to product toxicities and to develop novel strategies for increasing product safety. The long-term goal of his lab is to develop novel strategies to increase safety and efficacy of gene and cell therapy products.

General Overview

Viral vector-based or cell-based gene therapies hold great potential for treating many human diseases. However, challenges such as host immune responses and inflammatory toxicities associated with these therapies can impede its development and widespread use. Pre-existing immunity against viruses used in gene therapies, de novo immune responses against viral vectors and transgene products, and inflammatory toxicities associated with CAR-T cell therapies, are some of the major challenges that must be addressed. The ability of these products to induce immune responses and inflammation (product immunogenicity) is a safety risk to patients and can also limit product efficacy. Thus, there is a need for novel strategies for reducing the immunogenicity of gene therapy products in order to improve their safety and efficacy.

Currently, we are studying the underlying mechanisms that trigger immune responses during gene therapy with viral vectors (e.g. lentiviral and AAV) and developing various strategies to reduce product immunogenicity. Our previous studies identified novel mechanisms of host immune modulation by RNA viruses. We are using these viral strategies to reduce the immunogenicity of gene therapy vectors. We are also studying mechanisms contributing to severe inflammation and toxicity during CAR-T cell therapies and developing strategies to reduce CAR-T cell product toxicities.

This work addresses a very important public health issue. Gene therapy with viral vectors or CAR-T cells have shown great potential to treat many human diseases, such as cancer, genetic diseases, chronic viral infections, and autoimmune diseases. However, host immune responses against these products can negatively affect product safety and efficacy. The innovation of our research relates to 1) using natural viral immunomodulatory strategies to reduce unwanted host immune responses against gene therapy vectors and 2) developing novel strategies to increase safety and efficacy of CAR-T cell therapy.

The scientific knowledge obtained from these studies might also help to evaluate the safety and efficacy of gene therapy product applications submitted to the FDA as well as help manufactures to improve the safety and efficacy of these products.

Scientific Overview

T cell receptor (TCR) signaling is required for T cell activation and development of T cell response against gene therapy vectors; it is also required for chimeric antigen receptor (CAR) T cell activation and function. Thus, understanding mechanisms regulating TCR signaling might help to develop strategies for reducing host immune responses during gene therapy or inflammation during CAR-T cell therapy.

One of the goals of our research program is to develop strategies to reduce host immune responses against viral vectors during gene therapy. Our previous studies on RNA viruses, such as hepatitis C virus (HCV) and Yellow Fever virus (YFV), identified novel mechanisms by which these viruses dampen host T cell response. We identified highly conserved immunomodulatory motifs in the viral protein and RNA that interfere with TCR signaling pathways. One mechanism is viral-RNA-mediated suppression of tyrosine phosphatase epsilon (PTPRE) expression, which impairs Lck activation. PTPRE is a novel regulator of TCR function and in cells expressing HCV and YFV RNA, PTPRE expression is reduced, impairing T cell function. Furthermore, PTPRE expression in liver tissue and peripheral blood mononuclear cells from HCV-infected or YFV-vaccinated humans is lower than that of controls. In preclinical studies, PTPRE expression in the liver and splenocytes of mice infected with YFV is reduced compared to mice infected with control (mumps) virus. In addition, inhibition of PTPRE by YFV in mice reduced the T cell response against heterologous antigen (ovalbumin) compared to uninfected or mumps-infected mice. Together, these studies suggest that inhibition of TCR signaling, either by viral-protein- mediated inhibition of Lck function or viral-RNA-mediated inhibition of PTPRE expression might reduce T cell response against heterologous antigens. Currently, we are developing novel strategies based on these viral immunomodulatory factors to reduce T cell response against gene therapy vectors and transgene products. Since T cell signaling plays an essential role in developing adaptive immune responses, inhibition of this signaling pathway might reduce both the T and B cell responses against gene therapy vectors.

We are also studying the underlying mechanisms for inflammatory toxicities during CAR-T cell therapy. Following activation of CAR-T cells, bystander immune cells such as monocytes and macrophages are also activated. Inflammatory factors (e.g. IL-6, IL-1β) released by activated myeloid cells contribute to severe inflammation and toxicity during CAR-T cell therapy. Treatment modalities that block such inflammatory factors, such as tocilizumab (anti-IL6R), anakinra (anti-IL1R) or steroids, are commonly used to manage severe inflammation. However, there are limitations with these therapies: steroids can impair CAR-T cell function and patients can develop tocilizumab-refractory cytokine release syndrome (CRS). Furthermore, these agents can have heterogeneous response in the human population. Furthermore, primary mechanisms leading to bystander immune cell activation and CRS/neurotoxicity development are not completely understood. Thus, there is a need to better understand underlying mechanisms contributing to inflammatory toxicities during CAR-T cell therapy. Our long-term goals are to understand mechanisms contributing to inflammatory toxicities during CAR-T cell therapy and develop novel strategies to improve safety and efficacy.

Publications

• J Infect Dis 2024 Mar 15;229(3):786-94 Characterization of "off-target" immune modulation induced by live attenuated yellow fever vaccine. Xiang J, Chang Q, McLinden JH, Bhattarai N, Welch JL, Kaufman TM, Stapleton JT
• J Immunother 2022 Apr;45(3):139-49 TCR-independent activation in presence of a Src-family kinase inhibitor improves CAR-T cell product attributes. Lamture G, Baer A, Fischer JW, Colon-Moran W, Bhattarai N
• Gene Ther 2022 Nov;29(10-11):616-23 A short hepatitis C virus NS5A peptide expression by AAV vector modulates human T cell activation and reduces vector immunogenicity. Colon-Moran W, Baer A, Lamture G, Stapleton JT, Fischer JW, Bhattarai N
• Front Immunol 2021 Jun 18;12:693016 CAR-T cell therapy: mechanism, management, and mitigation of inflammatory toxicities. Fischer JW, Bhattarai N
• Sci Rep 2018 Jul 19;8(1):10910 Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways. Baer A, Colon-Moran W, Bhattarai N
• PLoS One 2017 Oct 26;12(10):e0187123 Src-family kinases negatively regulate NFAT signaling in resting human T cells. Baer A, Colon-Moran W, Xiang J, Stapleton JT, Bhattarai N