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Current Stem Cell Research and Therapy

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The set of journals have been ranked according to their SJR and divided into four equal groups, four quartiles. Q1 (green) comprises the quarter of the journals with the highest values, Q2 (yellow) the second highest values, Q3 (orange) the third highest values and Q4 (red) the lowest values.

The SJR is a size-independent prestige indicator that ranks journals by their 'average prestige per article'. It is based on the idea that 'all citations are not created equal'. SJR is a measure of scientific influence of journals that accounts for both the number of citations received by a journal and the importance or prestige of the journals where such citations come from It measures the scientific influence of the average article in a journal, it expresses how central to the global scientific discussion an average article of the journal is.

Evolution of the number of published documents. All types of documents are considered, including citable and non citable documents.

This indicator counts the number of citations received by documents from a journal and divides them by the total number of documents published in that journal. The chart shows the evolution of the average number of times documents published in a journal in the past two, three and four years have been cited in the current year. The two years line is equivalent to journal impact factor ™ (Thomson Reuters) metric.

Evolution of the total number of citations and journal's self-citations received by a journal's published documents during the three previous years. Journal Self-citation is defined as the number of citation from a journal citing article to articles published by the same journal.

Evolution of the number of total citation per document and external citation per document (i.e. journal self-citations removed) received by a journal's published documents during the three previous years. External citations are calculated by subtracting the number of self-citations from the total number of citations received by the journal’s documents.

International Collaboration accounts for the articles that have been produced by researchers from several countries. The chart shows the ratio of a journal's documents signed by researchers from more than one country; that is including more than one country address.

Not every article in a journal is considered primary research and therefore "citable", this chart shows the ratio of a journal's articles including substantial research (research articles, conference papers and reviews) in three year windows vs. those documents other than research articles, reviews and conference papers.

Ratio of a journal's items, grouped in three years windows, that have been cited at least once vs. those not cited during the following year.

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PMC10295699

Stem Cell Therapy and Rejuvenation, and Their Impact on Society

1. introduction.

In his worldwide best-seller Homo Deus [ 1 ], historian and philosopher Yuval Noah Harari discusses the future challenges facing humankind. In particular, he predicts that humanity will pursue three goals in the coming decades: immortality, bliss, and divinity. Biomedical engineering is pivotal to at least two of these alleged human aspirations—immortality and divinity—and it may arguably pertain to the pursuit of bliss, as well. The possibility of replacing or upgrading cellular constituents of the human body has led to an unprecedented scenario; for the first time in history, new cells and body tissues can be generated ex vivo to replace damaged or decayed body parts via cell transplant, similarly to the replacement of pieces of a LEGO ®® figure. The use of stem cells for tissue/organ reconstruction and for the treatment of lesions and diseases has seen overwhelming success over the past few decades, and multiple well-validated therapies are now available for dealing with hitherto incurable conditions. These stem cell therapies may rely on both genetically modified and primary cells. Many, but not all, stem cell therapies fall into the category of biomedical engineering because they may include genetic manipulation, as well as sophisticated scaffold materials, innovative cell culture and delivery systems, and cell imaging and monitoring systems. With the abundant public and private funding contributed to achieving this goal, the field of biomedical engineering is bound to grow substantially in the future. Furthermore, in the next few decades, researchers may even refine stem cell and tissue manipulation technology to such an extent as to prevent or delay cellular decay associated with aging, which brings us to the concept of cell rejuvenation. Although we are arguably still quite far from the point of generating eternally young, a-mortal humans, many renowned scientists are fully dedicated to studying the mechanisms of cellular aging and rejuvenation, many of whom are hired by private biotechnology companies with incredibly large amounts of funding available. This editorial seeks to discuss the main features, advantages, and limitations of stem cell therapies in combination with cellular rejuvenation strategies, and their impact on society. Paradoxically, despite its role in addressing important challenges that could influence the future of humankind, the social impact of stem cell therapy research, measured in terms of improved healthcare outcomes, will only become evident many years, or even decades, after it has been tested in experimental models at the laboratory level.

2. Stem Cell Therapies for Tissue Healing and Regeneration

Stem cells possess two distinct features: (i) self-renewal, or the ability to sustain successive rounds of cell division, and (ii) potency, or the ability to give rise to other specialized cell types. According to this principle, stem cells can be classified as totipotent, pluripotent, multipotent, or unipotent [ 2 ]. Most mature cells in the human body are highly specialized (differentiated) and have lost their ability to undergo cell division; hence, they are also referred to as “post-mitotic cells”. When differentiated post-mitotic cells die as a result of natural aging or lesions/disease, they must be regenerated through the activation of local stem cells, which are often tissue-specific and restricted to particular niches in the adult body [ 2 , 3 ]. Adult tissues vary greatly in their self-renewal rates, with some tissues harboring an abundant, highly proliferative population of stem cells (for example, the gastrointestinal and skin epithelia and bone marrow) whereas others contain relatively quiescent stem cell populations that can be activated in response to injury, such as muscles and the central nervous system [ 4 ]. Natural tissue renewal depends on these adult tissue-specific stem cells, which can be harvested for ex vivo expansion, and the development of Tissue Engineering Therapies [ 5 ]. Alternatives to adult-tissue stem cells are embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), but their use in regenerative therapies is largely limited by ethical and safety constraints, respectively [ 6 , 7 ].

Since the discovery of bone marrow stem cells as the healing component of bone marrow transplants against hematological disorders in the 1960s, the stem cell research field has expanded considerably, and it is expected to continue to do so in the future. Many excellent review articles have been published in this journal over the last few years, showing progress in the use of stem cells for the treatment of a variety of diseases and conditions, such as Diabetes Mellitus [ 8 ], ischemic stroke [ 9 ], infectious diseases [ 10 ], and wounds [ 11 ]. The benefits of stem cell therapy include both cell replacement and paracrine mechanisms. A prevalent line of research at the moment is the use of stem cell-secreted extracellular vesicles, which avoid most of the major risks associated with long-term cell transplantation [ 12 ]. Stem cells can also be genetically modified for a particular application, such as curing a congenital disease [ 13 ]. This brings up the issue of stem cell modification and enhancement, with potential applications that could extend beyond their use in disease therapy.

3. Stem Cell Rejuvenation

One obvious problem with stem cell therapies is the onset of cellular senescence, in which cells lose their ability to divide and self-renew. This phenomenon is closely related to aging, and may have different causes, such as excessive accumulated population doubling (replicative senescence) and genotoxic, oxidative, and/or metabolic stress [ 14 , 15 ]. In addition, senescent cells show an altered secretome, which can have deleterious effects on tissues [ 16 ]. Stem cell senescence is a major limiting factor in tissue engineering, and several rejuvenation strategies have been devised to prevent or delay it. Some of the most effective rely on the genetic overexpression of “rejuvenating factors”, such as the widely known Yamanaka Factors OCT4, SOX2, KLF4, and CMYC (OSKM); Telomerase Reverse Transcriptase (TERT); or other transcription factors such as NANOG, YAP, and FOXD1 [ 15 , 17 ]. This approach has even been applied in vivo, where rejuvenation has been shown in different organs and at many levels following the forced overexpression of OSKM and other pluripotency-related transcription factors in transgenic mice [ 18 , 19 , 20 , 21 ].

Similarly to the development of artificial intelligence, the possibility of rejuvenating aging tissues and artificially extending the human lifespan could open up a Pandora’s box for humanity, with a myriad of both promising and questionable potential uses and implications. However, there is a limitation. At their current stage of development, these rejuvenation strategies depend on permanent genetic modification, which carries a high risk of side effects. For instance, Yamanaka factors are well-known for their reprogramming function, but they are also known to be highly oncogenic [ 22 ]. Thus, one major issue pertains to the cyclic induction of these rejuvenating factors; researchers must restrict their expression to the minimum required amount for the shortest possible duration and shut them off immediately afterwards using drug-inducible promoters [ 18 , 19 , 20 ].

Leaving aside the risks of genetic rejuvenation, other less radical approaches have been experimentally developed to enhance stem cell renewal and potency while delaying senescence. Those include the stimulation of autophagy [ 23 , 24 ] and hypoxia [ 25 , 26 ], and the pharmacological regulation of different signaling pathways such as mTOR [ 15 , 23 ], PI3K/AKT [ 27 , 28 ], or Wnt/β-catenin [ 29 , 30 ]. Notably, these treatments induce changes at the epigenetic level, indirectly resulting in the higher expression of OSKM and other reprogramming factors by stem cells, but with fewer side effects than traditional reprogramming methods. The limitation is that these pharmacological and/or metabolic interventions may induce a more subtle and much less consistent rejuvenation phenotype than outright genetic OSKM overexpression. Regardless of the rejuvenation methodology chosen, a final constraint that has received relatively little attention so far is the accumulation of somatic mutations in stem cells. If stem cells are artificially induced to bypass senescence mechanisms, one likely long-term consequence is the induction of tumorigenesis [ 31 ]. After all, senescence is a natural mechanism intended to prevent the propagation of malignant or irreversibly damaged cells. It is unclear how somatic gene mutations associated with normal aging might interact in the context of the cellular overexpression of reprogramming factors.

Nevertheless, research continues, and the understanding of the aging process and the development of new strategies for organism rejuvenation are the objectives of powerful and generously funded private companies such as Rejuvenate Bio ( https://rejuvenatebio.com/ ), Calico Labs ( https://www.calicolabs.com/ ), and Altos Labs ( https://altoslabs.com/ ). Given the importance of the issue at hand, it is possible that these and other related research companies will continue to fare well in the future. In any case, it is likely that if an “organism rejuvenation therapy” becomes available, it will be restricted to the very wealthy, given the high costs associated with these technologies.

4. Research on Stem Cell Therapies: The Long-Term Social Impact

Those familiar with stem cell-based therapies may understand the long and difficult road that precedes a promising discovery at the laboratory level, at which point researchers will seek to translate it to clinical practice in the form of an Advanced Therapeutic Medicinal Product (ATMP). In their review article published in Bioengineering in 2022, Muthu et al. [ 32 ] present many of the regulatory challenges that apply to such cases, including the funding of extremely expensive clinical trials under Good Manufacturing Practice (GMP) laboratory standards. The reason for this regulatory complexity is that we are dealing with the most complicated and unpredictable medicaments of all: live cells and tissues. Paradoxically, this difficulty regarding translation into clinical practice could constitute an obstacle to the social recognition of this research, since few of the many stem cell therapies that are developed at the experimental level reach the clinic and are translated into effective improvements in the clinical management of patients. Additionally, the experimental therapies that do succeed take a long time to reach patients.

Impact assessment in health sciences is an important process for assessing the effectiveness and usefulness of biomedical research in improving healthcare outcomes. Accordingly, research on issues such as organ regeneration and rejuvenation could be regarded as having major potential health impacts. However, stem cell research produces results regarding social impact over a relatively long time scale of many years, or even decades. Thus, it is important to also consider the context and purpose of the research being assessed [ 33 , 34 ]. We must recognize and promote the interconnectedness of preclinical and clinical research as a major way to generate a meaningful social impact, as advances in preclinical research often pave the way for clinical trials and the development of new therapies. Unquestionably, research on stem cell therapies combined with cell rejuvenation could have a substantial long-term impact on society.

5. Conclusions

There is no doubt that stem cell therapies combined with biomedical engineering and cell rejuvenation could have a considerable and permanent impact on humanity. Arguably, the process of developing rejuvenation therapies is in its infancy, and it could take a long time for them to become a reality. However, the same was once true of other diseases and lesions that can be now cured using stem cell transplants. Downplaying the social impact of stem cell therapies may affect public resource allocation to this field, but such research will continue nonetheless with the support of private funding.

Funding Statement

This research was funded by a Basque Government Grant to Consolidated Research Groups/Ikerketa Taldeak (IT1751-22).

Conflicts of Interest

The author declares no conflict of interest.

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Stem Cell Research and Therapy - Impact Score, Ranking, SJR, h-index, Citescore, Rating, Publisher, ISSN, and Other Important Details

Published By: BioMed Central Ltd.

Abbreviation: Stem Cell Res. Ther.

Impact Score The impact Score or journal impact score (JIS) is equivalent to Impact Factor. The impact factor (IF) or journal impact factor (JIF) of an academic journal is a scientometric index calculated by Clarivate that reflects the yearly mean number of citations of articles published in the last two years in a given journal, as indexed by Clarivate's Web of Science. On the other hand, Impact Score is based on Scopus data.

Important details, about stem cell research and therapy.

Stem Cell Research and Therapy is a journal published by BioMed Central Ltd. . This journal covers the area[s] related to Biochemistry, Genetics and Molecular Biology (miscellaneous), Cell Biology, Medicine (miscellaneous), Molecular Medicine, etc . The coverage history of this journal is as follows: 2010-2022. The rank of this journal is 2140 . This journal's impact score, h-index, and SJR are 7.16, 106, and 1.498, respectively. The ISSN of this journal is/are as follows: 17576512 . The best quartile of Stem Cell Research and Therapy is Q1 . This journal has received a total of 11541 citations during the last three years (Preceding 2022).

Stem Cell Research and Therapy Impact Score 2022-2023

The impact score (IS), also denoted as the Journal impact score (JIS), of an academic journal is a measure of the yearly average number of citations to recent articles published in that journal. It is based on Scopus data.

Prediction of Stem Cell Research and Therapy Impact Score 2023

Impact Score 2022 of Stem Cell Research and Therapy is 7.16 . If a similar downward trend continues, IS may decrease in 2023 as well.

Impact Score Graph

Check below the impact score trends of stem cell research and therapy. this is based on scopus data., stem cell research and therapy h-index.

The h-index of Stem Cell Research and Therapy is 106 . By definition of the h-index, this journal has at least 106 published articles with more than 106 citations.

What is h-index?

The h-index (also known as the Hirsch index or Hirsh index) is a scientometric parameter used to evaluate the scientific impact of the publications and journals. It is defined as the maximum value of h such that the given Journal has published at least h papers and each has at least h citations.

Stem Cell Research and Therapy ISSN

The International Standard Serial Number (ISSN) of Stem Cell Research and Therapy is/are as follows: 17576512 .

The ISSN is a unique 8-digit identifier for a specific publication like Magazine or Journal. The ISSN is used in the postal system and in the publishing world to identify the articles that are published in journals, magazines, newsletters, etc. This is the number assigned to your article by the publisher, and it is the one you will use to reference your article within the library catalogues.

ISSN code (also called as "ISSN structure" or "ISSN syntax") can be expressed as follows: NNNN-NNNC Here, N is in the set {0,1,2,3...,9}, a digit character, and C is in {0,1,2,3,...,9,X}

Stem Cell Research and Therapy Ranking and SCImago Journal Rank (SJR)

SCImago Journal Rank is an indicator, which measures the scientific influence of journals. It considers the number of citations received by a journal and the importance of the journals from where these citations come.

Stem Cell Research and Therapy Publisher

The publisher of Stem Cell Research and Therapy is BioMed Central Ltd. . The publishing house of this journal is located in the United Kingdom . Its coverage history is as follows: 2010-2022 .

Call For Papers (CFPs)

Please check the official website of this journal to find out the complete details and Call For Papers (CFPs).

Abbreviation

The International Organization for Standardization 4 (ISO 4) abbreviation of Stem Cell Research and Therapy is Stem Cell Res. Ther. . ISO 4 is an international standard which defines a uniform and consistent system for the abbreviation of serial publication titles, which are published regularly. The primary use of ISO 4 is to abbreviate or shorten the names of scientific journals using the technique of List of Title Word Abbreviations (LTWA).

As ISO 4 is an international standard, the abbreviation ('Stem Cell Res. Ther.') can be used for citing, indexing, abstraction, and referencing purposes.

How to publish in Stem Cell Research and Therapy

If your area of research or discipline is related to Biochemistry, Genetics and Molecular Biology (miscellaneous), Cell Biology, Medicine (miscellaneous), Molecular Medicine, etc. , please check the journal's official website to understand the complete publication process.

Acceptance Rate

Interest/demand of researchers/scientists for publishing in a specific journal/conference.
The complexity of the peer review process and timeline.
Time taken from draft submission to final publication.
Number of submissions received and acceptance slots
And Many More.

The simplest way to find out the acceptance rate or rejection rate of a Journal/Conference is to check with the journal's/conference's editorial team through emails or through the official website.

Frequently Asked Questions (FAQ)

What is the impact score of stem cell research and therapy.

The latest impact score of Stem Cell Research and Therapy is 7.16. It is computed in the year 2023.

What is the h-index of Stem Cell Research and Therapy?

The latest h-index of Stem Cell Research and Therapy is 106. It is evaluated in the year 2023.

What is the SCImago Journal Rank (SJR) of Stem Cell Research and Therapy?

The latest SCImago Journal Rank (SJR) of Stem Cell Research and Therapy is 1.498. It is calculated in the year 2023.

What is the ranking of Stem Cell Research and Therapy?

The latest ranking of Stem Cell Research and Therapy is 2140. This ranking is among 27955 Journals, Conferences, and Book Series. It is computed in the year 2023.

Who is the publisher of Stem Cell Research and Therapy?

Stem Cell Research and Therapy is published by BioMed Central Ltd.. The publication country of this journal is United Kingdom.

What is the abbreviation of Stem Cell Research and Therapy?

This standard abbreviation of Stem Cell Research and Therapy is Stem Cell Res. Ther..

Is "Stem Cell Research and Therapy" a Journal, Conference or Book Series?

Stem Cell Research and Therapy is a journal published by BioMed Central Ltd..

What is the scope of Stem Cell Research and Therapy?

Biochemistry, Genetics and Molecular Biology (miscellaneous)
Cell Biology
Medicine (miscellaneous)
Molecular Medicine

For detailed scope of Stem Cell Research and Therapy, check the official website of this journal.

What is the ISSN of Stem Cell Research and Therapy?

The International Standard Serial Number (ISSN) of Stem Cell Research and Therapy is/are as follows: 17576512.

What is the best quartile for Stem Cell Research and Therapy?

The best quartile for Stem Cell Research and Therapy is Q1.

What is the coverage history of Stem Cell Research and Therapy?

The coverage history of Stem Cell Research and Therapy is as follows 2010-2022.

Credits and Sources

Scimago Journal & Country Rank (SJR), https://www.scimagojr.com/
Journal Impact Factor, https://clarivate.com/
Issn.org, https://www.issn.org/
Scopus, https://www.scopus.com/

Note: The impact score shown here is equivalent to the average number of times documents published in a journal/conference in the past two years have been cited in the current year (i.e., Cites / Doc. (2 years)). It is based on Scopus data and can be a little higher or different compared to the impact factor (IF) produced by Journal Citation Report. Please refer to the Web of Science data source to check the exact journal impact factor ™ (Thomson Reuters) metric.

Impact Score, SJR, h-Index, and Other Important metrics of These Journals, Conferences, and Book Series

Check complete list

Stem Cell Research and Therapy Impact Score (IS) Trend

Top journals/conferences in biochemistry, genetics and molecular biology (miscellaneous), top journals/conferences in cell biology, top journals/conferences in medicine (miscellaneous), top journals/conferences in molecular medicine.

Scientometrics

Stem cell research and therapy, biology , cell biology, how influential is stem cell research and therapy.

Open access
Published: 22 April 2024

The potency of mesenchymal stem/stromal cells: does donor sex matter?

Ghada Maged 1 ,
Menna A. Abdelsamed 2 ,
Hongjun Wang 3 , 4 &
Ahmed Lotfy ORCID: orcid.org/0000-0001-9928-0724 3

Stem Cell Research & Therapy volume 15 , Article number: 112 ( 2024 ) Cite this article

165 Accesses

Metrics details

Mesenchymal stem/stromal cells (MSCs) are a promising therapeutic tool in cell therapy and tissue engineering because of their multi-lineage differentiation capacity, immunomodulatory effects, and tissue protective potential. To achieve optimal results as a therapeutic tool, factors affecting MSC potency, including but not limited to cell source, donor age, and cell batch, have been investigated. Although the sex of the donor has been attributed as a potential factor that can influence MSC potency and efficacy, the impact of donor sex on MSC characteristics has not been carefully investigated. In this review, we summarize published studies demonstrating donor-sex-related MSC heterogeneity and emphasize the importance of disclosing donor sex as a key factor affecting MSC potency in cell therapy.

Introduction

Mesenchymal stem/stromal cells (MSCs) are multipotent adult stem cells that can be obtained from various tissues, such as adipose tissue, bone marrow, umbilical cords, and other sources. MSCs are a popular source of cell therapy in regenerative medicine due to their multi-lineage differentiation capacity, immunomodulatory effects, and tissue protective potential [ 1 ]. In vitro, MSCs can proliferate and differentiate into various cell types, including adipocytes, osteoblasts, chondrocytes, and others. When infused in vivo, MSCs can replace damaged cells and tissues [ 2 , 3 , 4 ]. MSCs can also secrete growth factors, extracellular vesicles, and mitochondria that promote the survival of other cells through paracrine effects [ 5 , 6 ]. These unique characteristics have attracted dramatic attention to MSCs as an efficient therapeutic tool [ 7 ].

To date, the therapeutic effects of MSCs have been tested in many animal models and more than 1,138 human clinical trials [ 8 ]. Even though promising results were observed in different preclinical animal disease models, most of the MSC clinical trials for various human diseases have not achieved their anticipated outcomes; this discrepancy could be attributed to inconsistent MSC criteria or, in other words, MSC heterogeneity [ 9 ].

MSCs exhibit biological heterogeneity based on several criteria, including donor age, source of donor tissue, as well as differences found in cell clones and batches. For example, MSCs derived from younger donors are more potent than those from elderly donors. Likewise, MSCs from separate sources such as bone marrow (BM-MSCs) or adipose tissue (ASCs) also differ in certain aspects, e.g., ASCs have a higher proliferation rate than BM-MSCs [ 10 , 11 , 12 , 13 ].

Due to the increasing demand for cell-based therapy, it is imperative to assess additional factors affecting the potency of MSCs. Donor sex has recently been recognized as a factor affecting MSC characterization, potency, and therapeutic efficiency. In this review, we discuss factors that contribute to MSC heterogeneity and potency with an emphasis on published studies describing the impact of donor sex on MSC proliferation, differentiation capabilities, gene expression, and therapeutic effects.

MSC Heterogeneity

The heterogeneity of MSCs can arise from various donor-related factors, such as donor age and tissue sources, or non-donor-related factors, such as cell batch; passage; and freezing/thawing process (Fig. 1 ) [ 14 , 15 , 16 , 17 ]. Below are examples of how these factors could result in MSC heterogeneity and affect their potency when used in disease therapy.

Factors that can contribute to MSCs heterogeneity

First, donor age is considered a quintessential factor that should be considered when using MSCs in cell therapies. The potency of MSCs declines with age. For instance, ASCs from elderly human donors (> 60 years) displayed more senescent features with reduced differentiation potential and produced fewer colonies when compared to younger donors (< 30 years) [ 11 ]. Older age also showed a negative effect on the yield of BM-MSCs in rats, with the younger age (4 weeks) having the maximum yield of MSCs compared to 48-week-old rats [ 12 ]. Therefore, strategies such as licensing might be needed to enhance the yield, cell proliferation, and expansion capabilities of MSCs from aged donors if autologous cells are used [ 11 ]. A study by Li and colleagues showed human MSCs isolated from aged donors (65–80 years old) showed a lower expression of fibroblast growth factor 2 (FGF2) and a higher level of senescent activity than MSCs isolated from younger donors (18–25 years old) [ 13 ]. Another study also demonstrated a significant decline in the quantity of MSCs in bone marrow associated with older age due to the decrease in bone density [ 18 ].

The tissue source from which MSCs are derived can also contribute to their heterogeneity. Specifically, MSCs obtained from different tissues could exhibit variations in their differentiation potential, proliferation rate, immunomodulatory properties, and gene expression profiles [ 16 , 19 ]. For instance, BM-MSCs and ASCs show greater penchants to differentiate into osteoblasts and better colony-forming abilities than umbilical cord-derived MSCs (UC-MSCs). On the other hand, UC-MSCs have a higher proliferation rate and a higher tendency toward chondrogenic differentiation than BM-MSCs and ASCs [ 20 ]. There is also heterogeneity between human ASCs and human BM-MSCs, as approximately 1,400 genes related to tenogenic potential and chemotaxis exhibited differences between these two types of cells. Lastly, although adequate chondrogenesis has been demonstrated by both dental pulp-derived MSCs (DPSCs) and periodontal ligament-derived MSCs, DPSCs uniquely show a higher tendency towards both osteogenesis and adipogenesis [ 21 ].

The impact of donor sex on MSC heterogeneity and potency

Recent studies have revealed that the characteristics of MSCs could vary depending on the donor’s sex (summary of human MSC studies in Table 1 and animal MSC studies in Table 2 ). We discuss the differences between MSCs from male and female donors and how donor sex impacts proliferation, differentiation capability, gene expression, immunomodulatory and therapeutic effects, and other biological characteristics of MSCs.

MSC Proliferation

One of the MSCs features is the in vitro proliferation [ 1 , 22 , 23 , 24 ]. Among MSCs from different sources, BM-MSCs have been found to divide more rapidly when taken from younger females compared to those from males [ 25 ]. On the other hand, human UC-MSCs isolated from heterosexual twins showed that male fetal UC-MSCs had a significantly higher proliferation capacity than female fetal UC-MSCs, which has been attributed to higher expression levels of NANOG, TERT, OCT4, and SOX2 in UC-MSCs [ 26 ]. Moreover, assessing the gender–related characteristics in ASCs has also proven the gender-specific heterogeneity in MSC biology [ 27 , 28 ]. For example, ASCs from female donors show a greater ability to maintain their proliferative capacity in vitro than their male counterparts due to the higher expression of the OCT3/4 protein, a transcription factor indicative of the proliferative capacity of MSCs [ 27 ].

In a study of the steroid effect on BM-MSCs proliferation, it was reported that the optimal dose and interaction of steroids varied depending on donor sex. For instance, the mitogenic effects of estrogen on rat MSCs showed more pronounced effects in females with a concentration of 10 − 10 M-10 − 12 M 17β-estradiol (E2). However, combinations of estrogen and dexamethasone were more effective in promoting male rat MSC proliferation [ 29 ]. On the contrary, the optimal dose of E2 for the proliferation capacity of BM-MSCs derived from male and female mini-pigs was similar in both sexes and equal to 10 − 12 M [ 30 ]. Nonetheless, faster proliferation was observed in MSCs isolated from female rats than in male MSCs cultured in conventional or steroid-free media [ 29 ]. However, while female BM-MSCs have been shown to have beneficial properties, their use may contribute to an increase in the proliferation of breast cancer cells when cultured together. Therefore, caution should be exercised when considering the use of BM-MSCs in breast cancer therapy [ 31 ].

MSC differentiation capabilities

In vitro differentiation is one of the defining features of MSCs and can be measured by their ability to differentiate into osteogenic, chondrogenic, and adipogenic lineages under specific circumstances [ 4 ]. In addition, MSCs can differentiate into other cell types, such as skeletal myocytes and tenocytes, with the appropriate environmental cues [ 32 ]. Studies have been conducted to compare the gender-related differences in the MSC differentiation. A prime example is a study conducted on BM-MSCs which demonstrated that neither sex nor donor age affected the in vitro mesodermal differentiation capacity of BM-MSCs [ 25 ]. This study analyzed BM-MSC adipogenesis, osteogenesis, and chondrogenesis abilities respectively. No significant differences related to donor age or sex were observed [ 25 ]. On the other hand, a higher potential capacity for neurogenic differentiation at passage 10 was notable with an elevation of γ-aminobutyric acid (GABA) synthesis and release with female rhesus monkey BM-MSCs in comparison to nestin-positive male BM-MSCs due to a higher production of nestin-positive cells observed in the female BM-MSCs [ 33 ].

Under suitable conditions, ASCs exhibit the ability to undergo osteogenesis. Human ASCs from males and females were isolated from superficial and deep fatty layers of the abdominoplasty specimens and were cultured in osteogenic media. Markers for osteogenesis and their relations with sex were evaluated 1, 2, and 4 weeks after differentiation induction. Results showed a significant difference in the differentiation efficiency between male and female ASCs from both superficial and deep depots, with a higher degree in males than females. Furthermore, superficial male depot ASCs displayed faster and more efficient differentiation than their deep counterparts. On the contrary, the osteogenic differentiation degree was not significantly different between female ASCs from superficial or deep depots [ 34 ]. Moreover, in a mouse study, BM-MSCs from female mice showed lower osteogenesis than cells from male littermates [ 35 ].

Successful bone regeneration depends on various factors, with steroids functioning as an effective modulator regulating osteogenic differentiation. The regulatory effect of steroids is determined by the dose required for osteogenic markers up-regulation, which is sex-dependent. A higher activity of alkaline phosphatase (ALP), an early marker of osteogenic differentiation, was observed in female BM-MSCs treated with lower concentrations of E2, but not in male BM-MSCs [ 29 ]. In another study, the enrichment of BM-MSCs isolated from osteoporotic female donors with ALP and PDGFRα + /CD146 - /CD362 - cells had a greater than 50% likelihood of exhibiting increased differentiation capacity towards adipocyte formation, which is an undesirable outcome for bone tissue regeneration [ 36 ]. Nonetheless, Non-osteoporotic male donors who received vitamin D supplementation and had an enriched population of CD146 + /ALP + /CD14 - cells showed a more than 50% increase in their osteoblast differentiation capacity. Hence, non-osteoporotic males were more suitable for enhancing in vitro mineralized matrix formation than females [ 36 ]. On the other hand, the mature osteoblastic marker, osteocalcin, showed similar peak levels in both males and females. It suggests that the sex differences during osteogenic differentiation with E2 supplementation may be contributed to the variation in steroid receptors [ 29 ].

MSC Gene expression

Although male and female genomes are nearly identical, there are differences at the molecular level due to variations in gene expression [ 37 ]. Different chromosomic segments and gene expressions were also identified in human ASCs isolated from male and female donors by the transcriptome mapper (TRAM) meta-analysis. This finding resulted in a hypothesis that ASC characteristics such as differentiation, proliferation, modulation, and senescence may vary because of the donor sex of ASCs. Indeed, variations of expressions of inflammation-related genes including C-X-C motif ligands and immunoglobulin (e.g., Immunoglobulin Lambda Constant ( IGLC ) 1 and 3)) contributed to the variations in the immune modulatory capacity ASCs derived from male and female donors. While C-X-C motif ligands were expressed at a low level in males, IGLC1 and IGLJ3 (immunoglobulin lambda joining 3) were highly expressed compared to ASCs derived from females [ 38 ].

Previous studies have shown the integral role of CXCL3 in promoting adipogenic differentiation in mouse preadipocyte and MSC cell lines [ 39 ]. TRAM results indicate that female ASCs are likely to differentiate into adipocytes compared to male ASCs because of low abundance of CXCL3 in male cells [ 38 ]. In addition, stem cell proliferation and migration may differ between cells from each gender because of variations in the expression of cell cycle regulators such as TFPI2, GNG11, ANKK1 , and CAMTA1 .

Indoleamine 2, 3, dioxygenase (IDO) is critical for the immunosuppressive function of MSCs. Female BM-MSCs expressed higher levels of IDO1 compared to male BM-MSCs, suggesting a better capacity to suppress the proliferation of T cells [ 25 ]. On the other hand, there was no correlation between the expression of Oct4, Nanog, and Prdm14 mRNA and the donor’s sex or age in BM-MSCs [ 25 ]. However, the expression of the stemness-regulating gene Oct4 significantly differed between male and female MSCs derived from Wharton’s jelly [ 40 ]. Upregulation of Oct4 is associated with the upregulation of DNMT1. This methyltransferase plays a critical role in maintaining methylation patterns during DNA replication [ 41 ], with higher expression in males indicating a sex-dependent epigenetic modulation [ 40 ]. [].

MSCs secrete vascular endothelial growth factor A (VEGF-A) and transforming growth factor-β (TGF-β), which are both linked to in vitro and in vivo angiogenesis and anti-fibrotic processes [ 42 ]. A previous study revealed a notable difference in gender-based VEGF-A and TGF-β gene expression with a significant upregulation in male UC-MSCs compared to female UC-MSCs. As a result of this, it is reasonable to predict that male UC-MSCs may have better angiogenesis and anti-fibrotic processes potential than female UC-MSCs [ 26 ].

Immunomodulatory effect of MSCs

MSCs exert immunomodulatory and immunosuppressive effects through various mechanisms. They interact with immune cells such as T cells, B cells, and natural killer cells, modulating immune responses [ 43 , 44 ]. The immunomodulatory properties are attributed to the production of metabolites, cytokines, and growth factors by MSCs. The immune suppressive potential of MSCs involves cell-to-cell contact and the secretion of immune regulatory molecules [ 44 , 45 , 46 ].

The immunosuppressive properties of MSCs can also be manifested via paracrine effects of cell communication, cell adhesion molecules, and extracellular vesicles (EVs) [ 47 , 48 ]. For instance, in tissue injury caused by autoreactive T cells in autoimmune diseases, this type of cell communication is recruited to evoke immune response and EVs are carried to the site of inflammation by biofluids to modulate immunity [ 49 ]. MSCs have also been shown to produce several immunomodulatory factors including IL-10, IL-1 receptor antagonist (IL-1Ra), TGF-β and the cell adhesive molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [ 48 , 50 ] that mediate their immunosuppressive properties.

The impact of donor sex on the functionality and potency of MSCs, especially their immunomodulatory function, has been recently investigated. An in vitro study of ASCs from male and female human donors has shown that ASCs-mediated immunomodulation is likely donor-sex-specific [ 51 ]. Female ASCs produced significantly higher concentrations of the anti-inflammatory mediators IL-1Ra, PGE-2, and IDO than male ASCs. In addition, female ASCs showed prolonged expression of the adhesive molecule VCAM1 when compared to male ASCs. Female ASCs also promoted the downregulation of IL-2 receptor gene expression in PBMCs, leading to higher immunosuppression levels in comparison to male ASCs [ 51 ].

Sex-related immunosuppressive properties were also assessed in human BM-MSCs [ 25 ]. Interferon- γ receptor 1 (IFN-γR1) and IL-6β expression in female BM-MSCs were higher than their male counterparts. mRNA analysis has revealed a higher IDO1 mRNA expression in female than male BM-MSCs. In addition, female BM-MSCs exhibited a better immunosuppressive ability against T cell proliferation than male BM-MSCs. This suppression is suggested to be mediated by IDO1 [ 25 ]. On the contrary, a study by Zhang et al., has shown that there are no sex-related differences in immunosuppressive properties in UC-MSCs from heterosexual twins [ 26 ].

Therapeutic effect of MSCs

MSCs have therapeutic effects against many diseases because of their ability to regenerate and repair damaged tissues [ 4 ]. It was reported that multiple factors including donor sex affect the therapeutic efficacy of MSCs [ 52 ].

For instance, a study reported that the therapeutic efficacy of muscle-derived MSCs (MDSCs) for skeletal muscle regeneration is donor-sex dependent. Specifically, the regeneration potential of skeletal muscles was compared in vivo by transplanting male or female MDSCs into dystrophic mice. Subsequently, the data showed that female MDSCs could regenerate skeletal muscles more efficiently than their male counterparts [ 53 ].

It has also been evidenced that the chondrogenic and osteogenic differentiation potential of human MDSCs in bone and cartilage regeneration is donor sex-related [ 54 ]. Human MDSCs from male donors have been found to exhibit more chondrogenic and osteogenic potential than MDSCs from female donors in vitro. The in vivo tests of the two genders derived MDSCs further revealed that male MDSCs were more efficient in bone regeneration. Micro computed tomography (MicroCT) test showed more bone regeneration at 2 weeks with a higher bone density at 4 and 6 weeks after transplantation of male MDSCs compared to their female counterparts [ 54 ]. In contrast, no difference was observed between male and female donor MSCs when their therapeutic efficacies in recovering bone loss were compared in the gonadectomy mouse model in different recipient genders [ 55 ].

MSCs have presented therapeutic efficacy in neonatal hyperoxia-induced lung injury. Ibrahim Sammour and colleagues studied the effect of BM-MSC donor sex on the therapeutic potential of neonatal hyperoxia-induced lung injury [ 56 ]. The study revealed that BM-MSCs from female donors have a higher therapeutic potency than their male counterparts in attenuating inflammation in neonatal hyperoxia-induced lung injury. Female BM-MSCs are also superior to male MSCs in improving vascular remodeling [ 56 ]. Interestingly, the beneficial effect of the female MSCs is more preferential when given to male recipients [ 56 ].

Female MSCs have also been shown to exhibit a higher protective advantage than their male counterparts in sepsis and endotoxemia [ 57 ]. Manukyan et al. have examined the impact of donor sex on the therapeutic potential of MSCs in an endotoxemic cardiac dysfunction model in adult male Sprague-Dawley rats. By analyzing the myocardial functions of the injected rats, they found that female MSCs provided better protection of myocardial function than male MSCs [ 57 ]. In addition, the Bcl-xl/Bax ratio, an indicator for cell survival, is significantly increased after the treatment with female than male MSCs, suggesting a larger therapeutic potential of female MSCs than male MSCs against acute endotoxemic injury.

All these together underline that donor sex is a contributing factor affecting the therapeutic potential and potency of MSCs. The question is: “What factors determine the donor sex-related therapeutic potential?” Investigators argue that these reasons might be found in sex-related innate factors which are differentially expressed in male and female MSCs. The role of the sex-related hormone estrogen in providing the advantage of female MDSCs over male MDSCs in skeletal muscle regeneration has been tested. However, neither pre-stimulation of the male MDSCs with estrogen nor the transplantation of male MDSCs into female recipients improved the rate of skeletal muscle regeneration [ 53 ]. Male and female MDSCs were suggested to be able to respond to stress through different cellular pathways [ 53 ]. When MDSCs were exposed to oxidative stress, male MDSCs showed an increased differentiation rate while female MDSCs maintained a lower proliferation rate. Male MDSCs may have been depleted rapidly in the transplantation site, and female MDSCs would have a higher tissue regeneration ability than their male counterparts [ 53 ].

Other biological characteristics of MSCs

There are additional biological characteristics that expressed differences between male and female MSCs, including but not limited to cellular markers, cell senescence, sphingolipids levels, and even MSC quantities.

MSCs are heterogeneous cells with subpopulations that may influence their proliferative, pluripotent, and apoptotic features. Concerning donor sex, it has been revealed that diverse subpopulations may vary between cells from males and females. The pro and anti-inflammatory cytokine IL-6 has a higher expression in male than in female ASCs [ 27 ]. Moreover, there was a higher expression of the senescence-associated β-galactosidase (SA-β-Gal), a cell aging marker, in male ASCs than in their female counterpart [ 27 ]. The sex differences in cellular senescence have been reported in many other cell types and the causes are not clear yet; however, some factors such as sex chromosomes may play a role [ 58 ].

Interestingly, the quantity could differ between male and female MSCs. Strube P et al. showed that male rat bone marrow contained significantly higher BM-MSCs than female rats, represented by high colony-forming unit numbers in both femora and tibiae [ 59 ].

Assessing the profile of sphingolipids in BM-MSCs derived from different genders using liquid chromatography/tandem mass spectrometry revealed sex-related heterogeneity which may have contributed to differences in potency [ 60 ]. Male BM-MSCs have higher ratios of sphingomyelin, hexosylceramide and long-chain bases (LCBs) than their female counterparts (44.53%, 1,48% and 1.48% vs. 10.18%, 0.68% and 0.61%, respectively) whereas female BM-MSCs have a higher percentage of ceramides than their male counterparts (88.35% vs. 54%, respectively) [ 60 ]. The LCB profile of male BM-MSCs also differs from female BM-MSCs. In male BM-MSCs, LCBs consist of 23.64% sphingosine (Sph), 8.04% sphingosine-1- phosphate (S1P), 28.07% sphinganine (Sa), 6.18% sphingosine-1 phosphate (Sa1P), 21.84% glucosyl sphingosine (GlcSph) and 12.22% lysosphingomyelin (LSM). However, female BM-MSCs LCBs consist of 76% Sph, 4.59% S1P, 16.69% Sa, 2.57% Sa1P, and 0.15% LSM. These changes in LCB profile have its impact on cell’s biological functions. For instance, the increase in the S1P enhanced the therapeutic efficacy of MSCs in pulmonary arterial animal model hypertension [ 61 ].

Further perspective

The influence of MSC donor sex in MSCs heterogeneity and potency has yet to be carefully investigated. This review sheds light on the significance of considering the MSC donor sex-related characteristics that might give MSCs derived from one gender an advantage over the other as a therapeutic tool.

Defining these mechanisms of how MSCs from specific donor sex can differ from the other will uncover factors which can influence the therapy outcomes. Furthermore, some autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis, Sjogren’s syndrome, Grave’s disease, and Hashimoto’s thyroiditis, are prevalent in females. HIV infection also showed genetic disparities between males and females, and unequally affects women more than men [ 62 , 63 ]. Considering the encouraging results of MSCs and their clinical application in treating these conditions, we propose investigators report as many donor characteristics as possible, especially donor sex, that might contribute to the study outcomes when publishing their results. MSCs from a specific sex may have more therapeutic effects for these sex-biased diseases for a common reason. Consequently, since there are limited studies regarding the impact of sex on MSC-based cell therapy outcomes in these diseases, further investigations are necessary to optimize MSCs-based therapy. These studies will provide valuable insights for enhancing the treatment outcomes. As a result, after expanding our understanding of the interplay between donor or recipient sex and diseases and its significant impact on treatment results, the tailoring of cell therapies for diseases would become sex specific. In addition, to ascertain the sex specific MSCs safety and feasibility in diseases, it is essential to consider appropriate environmental cues in conjunction with sex to achieve the desired clinical outcomes. For example, female BM-MSCs and ASCs showed higher immunomodulation effects than male BM-MSCs and ASCs, which suggests that female BM-MSCs/ASCs are likely superior in treating autoimmune diseases than male BM-MSCs/ASCs (Fig. 2 ). On the other hand, male BM-MSCs and ASCs may have a greater osteogenic potential, suggesting they have better effect in treating bone disorders. Moreover, female BM-MSCs showed greater therapeutic potential against lung and cardiac injury than male counterparts in animal models, suggesting that female BM-MSCs would better treat lung or cardiac injuries (Fig. 2 ). Accordingly, it seems in the future, it will be beneficial to determine the MSC donor sex depending on the targeting disease.

Illustration of the main differences between male and female MSCs.

Over the last few decades, MSCs have been tested as a therapeutic tool in treating various diseases. However, their therapeutic effect varied mainly due to their heterogeneity. Although some studies listed in this review were only done with limited donors, they strongly suggest that donor sex is an important factor that contributes to MSC heterogeneity and potency, and emphasize the importance of considering donor sex when preparing MSC for animal studies or clinical trials to achieve optional therapeutic effects.

Data availability

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Abbreviations

Mesenchymal stem/stromal cells

Bone marrow mesenchymal stem cells

Adipose tissue derived stem cells

Peripheral blood mononuclear cell

Umbilical cord-derived MSCs

Dental pulp-derived MSCs

Lipopolysaccharide

Transcriptome mapper

β-estradiol

Fibroblast growth factor 2

Indoleamine 2, 3, dioxygenase

Alkaline phosphatase

Sphingosine

Sphingosine-1-phosphate

Sphinganine

Sphingosine-1 phosphate

Glucosyl sphingosine

lysosphingomyelin

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All figures were Created with BioRender.com.The authors would like to thank Michael Lee for language editing.

This study was supported by NIDDK grants 1R01DK105183, DK120394, DK118529, and the Department of Veterans Affairs, grant I01BX004536.

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Department of Surgery, Medical University of South Carolina, 29425, Charleston, SC, USA

Hongjun Wang & Ahmed Lotfy

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Maged, G., Abdelsamed, M.A., Wang, H. et al. The potency of mesenchymal stem/stromal cells: does donor sex matter?. Stem Cell Res Ther 15 , 112 (2024). https://doi.org/10.1186/s13287-024-03722-3

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Heterogeneity