Estrogen Signaling Dictates Musculoskeletal Stem Cell Behavior: Sex Differences in Tissue Repair

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

Sex differences in the therapeutic effect of unaltered versus NFκB sensing IL-4 over-expressing mesenchymal stromal cells in a murine model of chronic inflammatory bone loss

“…Next, both in vitro and in vivo studies found sex differences in the function of musculoskeletal stromal cells and their response to estrogen treatment in various species (Knewtson et al, 2022). Bone is an endocrine tissue with androgen and estrogen receptors and steroid metabolizing enzymes; thus, sex hormones can Frontiers in Bioengineering and Biotechnology frontiersin.org demonstrate pronounced effects on bone homeostasis (Laurent et al, 2014).…”

Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model

“…Sex differences have been observed in musculoskeletal diseases. Although the reasons for these differences are complex and largely unknown, one of the possible reasons is the sex-based differences in cells’ response to the local microenvironment ( Knewtson et al, 2021 ). Sex differences have been shown to affect the MSC-based therapeutic potential for bone healing.…”

Roadmap on biomaterials for women’s health

“…Historically, research conducted on mechanisms of tissue repair and regeneration focused on male samples and pathologies that were assumed to be directly translated to female tissue and disease. However, an individual's biological sex significantly affects their ability to regenerate functional tissue [163]. Examples include the reduced ability for women to heal and regenerate new, healthy epidermis [164], cartilage [165], fibrocartilage [166], bone [167], skeletal muscle [168,169], smooth muscle [168,169], cardiac muscle [168,169], adipose [170], and neural tissue [171] after menopause, which results from a significant loss of sex hormone signaling and disproportionately enhances the risk for many degenerative diseases including osteoporosis, osteoarthritis, cardiovascular disease, and Alzheimer's disease.…”

“…Based on the NIH Office of Research on Women's Health's 2020 Strategic Plan [172], there is a push to 'incorporate findings of sex/gender differences in the design and application of new technologies, medical devices, and therapeutic drugs' . However, in a PubMed search of TE and regenerative medicine publications from 2019, only 28.4% of the 10 651 publications reported subject sex at all [163] (figure 15(A)). Of that subset of studies, only 38% reported using both male and female samples.…”