Why Gender-Specific Stem Cells Are Important

Gender in Stem Cell Biology: Impact on Cell Cycle Dynamics, Regenerative Potential and Immune Rejection of Adult Stem Cells

It is widely recognized that sex is an important biological variable that impacts biochemical, physiological and clinical outcomes (https://genderedinnovations.stanford.edu/case-studies/stem_cells.html#tabs-2). The National Institutes of Health has emphasized the necessity of understanding sex differences in pre-clinical research particularly as it pertains to the development of stem cell therapies. Performance of experiments that do not take into account sex can result in a lost opportunity to understand basic and developmental biology, and to develop the most appropriate cell-based therapies1.

Some of the well-established differences in the properties of female and male stem cells include:

Biochemical Differences: Sex differences exist in the activation of mesenchymal stem cells (MSC). Activation of MSCs differs between sexes, with XX cells producing more vascular endothelial growth factor (VEGF, which promotes cell proliferation) and less tumor necrosis factor alpha (TNF-α, which promotes inflammation and apoptosis) than XY cells when stressed with hypoxia, lipopolysaccharide (LPS), and hydrogen peroxide2, 3. Cytokine expression (IL-6, TNF) is higher, while VEGF expression is lower, in MSCs harvested from the bone marrow of male mice compared with female mice. In neural stem cells, estrogen receptor alpha (ERα) expression is greater in young male-derived cells, whereas estrogen receptor beta (ERβ) expression is greater in young female cells4, 5. Yuan et al.6 report that bone marrow stem cells from female nonhuman primates produce more nestin+ (neurogenic) cells, than from males, which may increase their ability to contribute to re-innervation of damaged tissues.

Differentiation Potential: With regards to neural fate and steroid receptors, neural stem cells (NSCs) obtained from young and old rats exhibited sexual dimorphism. Male cells preferentially differentiate into a neuronal or oligodendroglial fate, while cells from females have a propensity for an astrocytic lineage4, 5.

Regenerative Potential: Female BM-derived MSC have greater therapeutic efficacy than male MSC in reducing neonatal hyperoxia-induced lung inflammation and vascular remodeling7. The beneficial effects of female MSC’s were more pronounced in male animals. In muscle regeneration, even though all muscle-derived stem cells (MDSC) can differentiate into dystrophin-expressing fibers in vitro, only XX MDSCs can regenerate robustly in vivo8. Similarly, in the brain, MSCs from two year old female Rhesus monkeys have greater neurogenic capacity than MSCs from male monkeys6. There also are sex-based differences in vascular repair with bone marrow cell therapies. Unlike male mice, transplantation of mononuclear cells (MNCs) from female bone marrow into male atherosclerotic apolipoprotein E (ApoE) mice resulted in a reallocation of cytokines from proinflammatory to anti-inflammatory and hematopoeitic regulatory cytokines. This event corresponded with a decrease in plaques associated with atherosclerosis. A greater improvement in endogenous repair was detected following the same procedure in female atherosclerotic ApoE mice than that observed in male mice9.

Immune Considerations:  In humans, rejection of cell transplants has been noted between sexes10. A retrospective study of more than 50,000 patients who had received allogenic hematopoetic stem cell transplants showed that male patients who had been matched with female donors had worse outcomes than any other patient/donor gender combination. Specifically, female donor/male recipient patients experienced an increased rate of graft-versus-host disease (GvHD) and transplant related mortality (TRM). These patients also appeared to have a reduced risk of relapse, however this was not enough to offset the mortality associated with higher incidence of GvHD and TRM.

Sex Hormone Impact on Stem Cell Proliferation and Regeneration: There is evidence that certain sex hormones may influence the ability of cells to regenerate tissues. Hematopoietic stem cells in mice exhibit differences in cell-cycle regulation according to gender due to higher circulating estrogen11. While estradiol increases hematopoietic stem-cell division in both males and females, hematopoietic stem cells of female mice divide more frequently than male cells as a result of higher circulating estradiol. Pregnancy (increased estrogen) also results in increased frequency of hematopoietic stem cell division11. Sex hormones also affect muscle stem cell derived stem cell-mediated bone formation on bone formation with male cells producing greater volumes of bone in a bone defect model12.

These data indicate that the sex of stem cells may influence therapeutically relevant cell traits, such as proliferation and differentiation rates, regeneration, integration and therefore the success of stem cell therapies. Understanding the differences within and between XX and XY cells, and their interactions with hormonal environment, genetics, and epigenetics, will improve basic understanding of stem cell biology and the design of cell therapies for clinical trials.

References

  1. Beery AK, Zucker I. Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev. 2011;35(3):565-572.
  2. Crisostomo PR, Markel TA, Wang M, et al. In the adult mesenchymal stem cell population, source gender is a biologically relevant aspect of protective power. Surgery. 2007;142(2):215-221.
  3. Crisostomo PR, Wang M, Herring CM, et al. Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1). J Mol Cell Cardiol. 2007;42(1):142-149.
  4. Waldron J, McCourty A, Lecanu L. Neural stem cell sex dimorphism in aromatase (CYP19) expression: a basis for differential neural fate. Stem Cells Cloning. 2010;3:175-182.
  5. Waldron J, McCourty A, Lecanu L. Aging differentially affects male and female neural stem cell neurogenic properties. Stem Cells Cloning. 2010;3:119-127.
  6. Yuan J, Yu JX, Ge J. Sexual dimorphism on the neurogenic potential of rhesus monkeys mesenchymal stem cells. Biochem Biophys Res Commun. 2010;396(2):394-400.
  7. Sammour I, Somashekar S, Huang J, et al. The Effect of Gender on Mesenchymal Stem Cell (MSC) Efficacy in Neonatal Hyperoxia-Induced Lung Injury. PLoS One. 2016;11(10):e0164269.
  8. Deasy BM, Lu A, Tebbets JC, et al. A role for cell sex in stem cell-mediated skeletal muscle regeneration: female cells have higher muscle regeneration efficiency. J Cell Biol. 2007;177(1):73-86.
  9. Zenovich AG, Panoskaltsis-Mortari A, Caron GJ, et al. Sex-based differences in vascular repair with bone marrow cell therapy: relevance of regulatory and Th2-type cytokines. Transplant Proc. 2008;40(2):641-643.
  10. Stern M, Brand R, de Witte T, et al. Female-versus-male alloreactivity as a model for minor histocompatibility antigens in hematopoietic stem cell transplantation. Am J Transplant. 2008;8(10):2149-2157.
  11. Nakada D, Oguro H, Levi BP, et al. Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature. 2014;505(7484):555-558.
  12. Meszaros LB, Usas A, Cooper GM, et al. Effect of host sex and sex hormones on muscle-derived stem cell-mediated bone formation and defect healing. Tissue Eng Part A. 2012;18(17-18):1751-1759.

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