Cells within tissues are routinely subjected to physiological stress and strain, arising from direct interactions with neighboring cells as well as with extracellular matrix components. Accordingly, there is tremendous interest in deciphering how cells sense, and respond to, changes in biomechanical forces. In this study, we explored the effects of mechanostimulation on the differentiation of mouse female germline or oogonial stem cells (OSCs) as a model for adult stem cell function. We report that increasing levels, or repeated application of a subthreshold fixed level, of radial strain to OSCs in culture significantly increased rates of in vitro oocyte formation as a measure of stem cell differentiation. These responses involved changes in F-actin-mediated cytoskeletal tension as well as in activation of intracellular signaling by Rho-associated protein kinase (ROCK) and Yes-associated protein (YAP) phosphorylation. In addition, application of mechanical strain to OSCs enhanced association of YAP with muscle-specific cytidine-adenosine-thymidine (MCAT) response elements in the promoter stimulated by retinoic acid gene 8 (Stra8), the transcriptional activation of which is required for germline meiotic commitment. These data indicate that biomechanical strain directly promotes the differentiation of adult female germline stem cells through a signaling pathway involving F-actin, ROCK, YAP, and Stra8.

中文翻译：

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生物力学应变促进小鼠卵原干细胞分化

组织内的细胞通常会受到生理压力和应变，这是由于与邻近细胞以及细胞外基质成分的直接相互作用而产生的。因此，人们对破译细胞如何感知和响应生物力学力的变化产生了极大的兴趣。在这项研究中，我们探讨了机械刺激对小鼠雌性生殖系或卵原干细胞 (OSC) 分化的影响，作为成人干细胞功能的模型。我们报告增加水平，或重复应用阈下固定水平，径向应变对培养中的 OSC 显着增加体外卵母细胞形成率作为干细胞分化的衡量标准。这些反应涉及 F-肌动蛋白介导的细胞骨架张力的变化以及 Rho 相关蛋白激酶 (ROCK) 和 Yes 相关蛋白 (YAP) 磷酸化对细胞内信号传导的激活。此外，对 OSC 施加机械应变增强了 YAP 与启动子中肌肉特异性胞苷-腺苷-胸苷 (MCAT) 反应元件的关联由视黄酸基因 8 ( Stra8 ) 刺激，其转录激活是种系减数分裂承诺所必需的。这些数据表明，生物力学应变通过涉及 F-actin、ROCK、YAP 和 Stra8 的信号通路直接促进成年雌性生殖系干细胞的分化。