Abstract
Sexual dimorphisms in humans and other species exist in visually evident features such as body size and less apparent characteristics, including disease prevalence. Current research is adding to a growing understanding of sex differences in stem cell function and response to external stimuli, including sex hormones such as estrogens. These differences are proving significant and directly impact both the understanding of stem cell processes in tissue repair and the clinical implementation of stem cell therapies. Adult stem cells of the musculoskeletal system, including those used for development and repair of muscle, bone, cartilage, fibrocartilage, ligaments, and tendons, are no exception. Both in vitro and in vivo studies have found differences in stem cell number, proliferative and differentiation capabilities, and response to estrogen treatment between males and females of many species. Maintaining the stemness and reducing senescence of adult stem cells is an important topic with implications in regenerative therapy and aging. As such, this review discusses the effect of estrogens on musculoskeletal system stem cell response in multiple species and highlights the research gaps that still need to be addressed. The following evidence from investigations of sex-related phenotypes in adult progenitor and stem cells are pieces to the big puzzle of sex-related effects on aging and disease and critical information for both fundamental tissue repair and regeneration studies and safe and effective clinical use of stem cells.Impact StatementThis review summarizes current knowledge of sex differences in and the effects of estrogen treatment on musculoskeletal stem cells in the context of tissue engineering. Specifically, it highlights the impact of sex on musculoskeletal stem cell function and ability to regenerate tissue. Furthermore, it discusses the varying effects of estrogen on stem cell properties, including proliferation and differentiation, important to tissue engineering. This review aims to highlight the potential impact of estrogens and the importance of performing sex comparative studies in the field of tissue engineering.
Highlights
Studies of sex-based differences in humans have traditionally focused on visually evident features including body size, anatomical differences, and life span
Current research is adding to a growing understanding of sex differences in stem cell function and response to external stimuli, including sex hormones such as estrogens
3 Impact Statement This review summarizes current knowledge of sex differences in and the effects of estrogen treatment on musculoskeletal stem cells in the context of tissue engineering
Summary
Studies of sex-based differences in humans have traditionally focused on visually evident features including body size, anatomical differences, and life span. Some of the effects of E2 treatment have been linked to membrane-associated ERs. For example, the inhibition of chondrogenesis in male human BM-MSCs in 3D culture by E2 was tied to membrane-associated ERs such as GPR30 by Jenei-Lanzal et al.[44] Kamanga-Sollo et al found that though E2-stimulated increases in bovine satellite cell proliferation were mediated through classical ERs, increases in IGF-1 mRNA levels were controlled by GPR30.69 The PI3K/AKT pathway has been tied to E2 treatment-induced increases in proliferation rate[68] and cell number[75] of satellite cells and proliferation rate and expression of stemness-related genes in PDLSCs.[78] These results are not surprising given that PI3K/AKT activation leads to cell proliferation and that this pathway is closely linked to and can be activated by ER signaling.[92] Further, this pathway has been linked to the maintenance of the undifferentiated state of human embryonic stem cells and to differentiation of many 20 types of stem cells including ADSCs and PDLSCs, as discussed in a review by Ramazzotti et al.[93] Other pathways have been linked to the effects of estrogen treatment as well. Properly controlled studies of the effects of E2, other estrogens, and selective estrogen receptor modulators should be carried out to establish a deeper understanding of their potential roles in regenerative therapy
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