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W e have shown that muscle-derived stem cells (MDSCs) transplanted into dystrophic (mdx ) mice effi ciently regenerate skeletal muscle. However, MDSC populations exhibit heterogeneity in marker profiles and variability in regeneration abilities. We show here that cell sex is a variable that considerably influences MDSCs’ regeneration abilities. We found that the female MDSCs (F-MDSCs) regenerated skeletal muscle more effi ciently. Despite using additional isolation techniques and cell cloning, we could not obtain a male subfraction with a regeneration capacity similar to that of their female counterparts. Rather than being directly hormonal or caused by host immune response, this difference in MDSCs’ regeneration potential may arise from innate sex-related differences in the cells’ stress responses. In comparison with F-MDSCs, male MDSCs have increased differentiation after exposure to oxidative stress induced by hydrogen peroxide, which may lead to in vivo donor cell depletion, and a proliferative advantage for F-MDSCs that eventually increases muscle regeneration. These findings should persuade researchers to report cell sex, which is a largely unexplored variable, and consider the implications of relying on cells of one sex.
It will be interesting to determine whether other stem cell types also exhibit sex-related differences. In addition, stem cell experiments could have skewed results if male cells are selectively used for the purpose of in vivo cell tracking via the Y chromosome. This evidence that innate cellular sex differences may infl uence stem and progenitor biology should infl uence how researchers report and investigate the use of progenitor cells for regenerative medicine and the treatment of diseases.