The use of nanovibration to discover specific and potent bioactive metabolites that stimulate osteogenic differentiation in mesenchymal stem cells
The use of nanovibration to discover specific and potent bioactive metabolites that stimulate osteogenic differentiation in mesenchymal stem cells
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DOI：
10.1101/2020.02.07.938811
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发表时间：
2020-02
期刊：
影响因子：
13.6
通讯作者：
T. Hodgkinson;P. Tsimbouri;V. Llopis-Hernandez;P. Campsie;D. Scurr;Peter G. Childs;David Phillips;S. Donnelly;J. Wells;F. O'Brien;M. Salmerón-Sánchez;Karl E. V. Burgess;M. Alexander;M. Vassalli;R. Oreffo;S. Reid;David J. France;M. Dalby
中科院分区：
文献类型：
--
作者：
T. Hodgkinson;P. Tsimbouri;V. Llopis-Hernandez;P. Campsie;D. Scurr;Peter G. Childs;David Phillips;S. Donnelly;J. Wells;F. O'Brien;M. Salmerón-Sánchez;Karl E. V. Burgess;M. Alexander;M. Vassalli;R. Oreffo;S. Reid;David J. France;M. Dalby
成骨活性代谢物可以在纳米振动培养中被鉴定出来，并且它们的特异性和效力得到了提高。生物活性代谢物具有广泛的生物活性，是未来研究和治疗工具的潜在来源。在这里，我们使用纳米振动刺激来诱导间充质干细胞的成骨分化，在没有非靶点的非成骨分化的情况下。我们发现，这种不依赖于向培养基中添加外源生长因子的分化方法，提供了一种无伪影的方法来鉴定特异和有效地诱导成骨的生物活性代谢物。我们首先确定了一种高度特异的代谢物--硫酸胆固醇，这是一种内源性类固醇。接下来，对具有类似类固醇支架的其他小分子进行筛选，鉴定出具有特异和高度有效的成骨诱导活性的醋酸氟化可的松。此外，我们将细胞骨架的收缩能力作为成骨能力的衡量标准，并将细胞硬度作为特异性的衡量标准。这些发现表明，可以使用物理原理来鉴定生物活性代谢物，然后通过检查结构-功能关系来优化代谢物的效力。
Osteogenic activity metabolites can be identified in nanovibrational culture and have their specificity and potency enhanced. Bioactive metabolites have wide-ranging biological activities and are a potential source of future research and therapeutic tools. Here, we use nanovibrational stimulation to induce osteogenic differentiation of mesenchymal stem cells, in the absence of off-target, nonosteogenic differentiation. We show that this differentiation method, which does not rely on the addition of exogenous growth factors to culture media, provides an artifact-free approach to identifying bioactive metabolites that specifically and potently induce osteogenesis. We first identify a highly specific metabolite, cholesterol sulfate, an endogenous steroid. Next, a screen of other small molecules with a similar steroid scaffold identified fludrocortisone acetate with both specific and highly potent osteogenic-inducing activity. Further, we implicate cytoskeletal contractility as a measure of osteogenic potency and cell stiffness as a measure of specificity. These findings demonstrate that physical principles can be used to identify bioactive metabolites and then enable optimization of metabolite potency can be optimized by examining structure-function relationships.