Mechanotransduction is a strong driver of mesenchymal stem cell (MSC) fate. In vitro, variations in matrix mechanics invoke changes in MSC proliferation, migration and differentiation. However, when incorporating MSCs within injectable, inherently soft hydrogels, this dominance over MSC response substantially limits our ability to couple the ease of application of hydrogels with efficiently directed MSC differentiation, especially in the case of bone generation. Here, we identify differential miRNA expression in response to varying hydrogel stiffness and RhoA activity. We show that modulation of miR-100-5p and miR-143-3p can be used to bias MSC fate and provide mechanistic insight by demonstrating convergence on mTOR signalling. By modulating these mechanosensitive miRNAs, we can enhance osteogenesis in a soft 3D hydrogel. The outcomes of this study provide new understanding of the mechanisms regulating MSC mechanotransduction and differentiation, but also a novel strategy with which to drive MSC fate and significantly impact MSC-based tissue-engineering applications.

中文翻译：

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机械敏感的miRNA通过mTOR信号偏向人类间充质干细胞的命运。

机械转导是间充质干细胞（MSC）命运的强大驱动力。在体外，基质力学的变化会引起MSC增殖，迁移和分化的变化。但是，当将MSC掺入可注射的固有软性水凝胶中时，这种对MSC反应的支配性实质上限制了我们将水凝胶的应用简便性与有效定向的MSC分化相结合的能力，特别是在骨骼生成的情况下。在这里，我们确定了不同的miRNA表达，以响应不断变化的水凝胶硬度和RhoA活性。我们展示了miR-100-5p和miR-143-3p的调节可用于证明MSC的命运并通过展示mTOR信号的收敛性来提供机理上的见解。通过调节这些机械敏感的miRNA，我们可以在柔软的3D水凝胶中增强成骨作用。