Activation of AKT-mTOR Signaling Directs Tenogenesis of Mesenchymal Stem Cells
Activation of AKT-mTOR Signaling Directs Tenogenesis of Mesenchymal Stem Cells
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AKT-mTOR 信号传导的激活指导间充质干细胞的肌腱形成
DOI：
10.1002/stem.2765
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发表时间：
2018-04-01
期刊：
影响因子：
5.2
通讯作者：
Zhou, Yi Ting
中科院分区：
文献类型：
--
作者：
Cong, Xiao Xia;Rao, Xi Sheng;Zhou, Yi Ting
肌腱修复是临床上的一个挑战，因为对肌腱发生的了解有限。I型胶原和其他细胞外基质的合成对肌腱分化和动态平衡是必不可少的。目前关于肌腱发生的研究主要集中在肌腱发生的转录因子上，而在翻译水平上控制肌腱发生的信号还很少。在这里，我们发现雷帕霉素(MTOR)信号的机制靶点被蛋白生成生长因子、转化生长因子β1和胰岛素样生长因子-I激活。间充质干细胞(MSCs)在肌腱形成过程中mTOR表达上调。此外，mTOR在人类肌腱病组织中下调，并在他汀类药物治疗后失活。AKT或mTOR的抑制和耗竭均显著减少了I型胶原的产生，并损害了MSCs的肌腱形成。肌腱特异性消融mTOR导致肌腱缺损和I型胶原减少，但在转录水平上没有明显下调肌腱相关胶原的作用。我们的研究表明，AKT-mTOR轴是肌腱分化的关键介质，为肌腱病和肌腱损伤提供了一个新的治疗靶点。
Tendon repair is a clinical challenge because of the limited understanding on tenogenesis. The synthesis of type I collagen (Collagen I) and other extracellular matrix are essential for tendon differentiation and homeostasis. Current studies on tenogenesis focused mostly on the tenogenic transcriptional factors while the signaling controlling tenogenesis on translational level remains largely unknown. Here, we showed that mechanistic target of rapamycin (mTOR) signaling was activated by protenogenic growth factor, transforming growth factors beta1, and insulin-like growth factor-I. The expression of mTOR was upregulated during tenogenesis of mesenchymal stem cells (MSCs). Moreover, mTOR was downregulated in human tendinopathy tissues and was inactivated upon statin treatment. Both inhibition and depletion of AKT or mTOR significantly reduced type I collagen production and impaired tenogenesis of MSCs. Tendon specific-ablation of mTOR resulted in tendon defect and reduction of Collagen I. However, there is no evident downregulation of tendon associated collagens at the transcription level. Our study demonstrated that AKT-mTOR axis is a key mediator of tendon differentiation and provided a novel therapeutic target for tendinopathy and tendon injuries.