Abstract
BackgroundSmooth muscle progenitor cells (pSMCs) differentiated from human pluripotent stem cells (hPSCs) hold great promise for treating diseases or degenerative conditions involving smooth muscle pathologies. However, the therapeutic potential of pSMCs derived from men and women may be very different. Cell sex can exert a profound impact on the differentiation process of stem cells into somatic cells. In spite of advances in translation of stem cell technologies, the role of cell sex and the effect of sex hormones on the differentiation towards mesenchymal lineage pSMCs remain largely unexplored.MethodsUsing a standard differentiation protocol, two human embryonic stem cell lines (one male line and one female line) and three induced pluripotent stem cell lines (one male line and two female lines) were differentiated into pSMCs. We examined differences in the differentiation of male and female hPSCs into pSMCs, and investigated the effect of 17β-estradiol (E2) on the extracellular matrix (ECM) metabolisms and cell proliferation rates of the pSMCs. Statistical analyses were performed by using Student’s t test or two-way ANOVA, p < 0.05.ResultsMale and female hPSCs had similar differentiation efficiencies and generated morphologically comparable pSMCs under a standard differentiation protocol, but the derived pSMCs showed sex differences in expression of ECM proteins, such as MMP-2 and TIMP-1, and cell proliferation rates. E2 treatment induced the expression of myogenic gene markers and suppressed ECM degradation activities through reduction of MMP activity and increased expression of TIMP-1 in female pSMCs, but not in male pSMCs.ConclusionshPSC-derived pSMCs from different sexes show differential expression of ECM proteins and proliferation rates. Estrogen appears to promote maturation and ECM protein expression in female pSMCs, but not in male pSMCs. These data suggest that intrinsic cell-sex differences may influence progenitor cell biology.
Highlights
Smooth muscle progenitor cells differentiated from human pluripotent stem cells hold great promise for treating diseases or degenerative conditions involving smooth muscle pathologies
Differentiation of Human pluripotent stem cell (hPSC) into Smooth muscle progenitor cell (pSMC) To examine the influence of cell sex on the differentiation capability of hPSCs, the hPSCs were induced toward the Smooth muscle cell (SMC) fate
During in-vitro differentiation, we did not observe any differences between the male (n = 2) and the female (n = 3) lines, assessed by the percentage of the intermediate CD34+/CD31+ vascular progenitor cells (VPCs) and the cell morphological evolution during differentiation (Fig. 1b). These observations suggest that cell sex does not affect the differentiation capability of hPSCs into Vascular progenitor cell (VPC)
Summary
Smooth muscle progenitor cells (pSMCs) differentiated from human pluripotent stem cells (hPSCs) hold great promise for treating diseases or degenerative conditions involving smooth muscle pathologies. When SMCs are injured, rather than regenerating they are partially replaced by fibroblasts and scar tissue [1] Over time, these injuries can result in compromised function and in a wide range of diseases involving the urological [2], cardiovascular [3], or gastrointestinal systems [4]. Endothelial cells in the nascent hollow organs recruit smooth muscle progenitor cells (pSMCs) to be invested in tubular walls [5]. Because of their unexhausted differentiation and proliferation potential, pSMCs are thought to have better therapeutic efficacy compared with mature SMCs [6, 7]. The existence of pSMCs in adult organs remains controversial and the number of resident pSMCs in reported studies is too low to be isolated and purified for regenerative therapy [9, 10]
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