Activation of AKT-mTOR Signaling Directs Tenogenesis of Mesenchymal Stem Cells,STEM CELLS

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Activation of AKT-mTOR Signaling Directs Tenogenesis of Mesenchymal Stem Cells
STEM CELLS ( IF 4.0 ) Pub Date : 2018-01-05 , DOI: 10.1002/stem.2765
Xiao Xia Cong _{1,

2} , Xi Sheng Rao _{1,

2} , Jun Xin Lin ₂ , Xiao Ceng Liu _{1,

2} , Guang An Zhang _{1,

2} , Xiu Kui Gao _{1,

2} , Min Yi He _{1,

2} , Wei Liang Shen _{2,

3} , Wei Fan _{1,

2} , Dominique Pioletti ₄ , Li Ling Zheng _{1,

2} , Huan Huan Liu ₂ , Zi Yin ₂ , Boon Chuan Low ₅ , Ronen Schweitzer ₆ , Hongwei Ouyang _{2,

7} , Xiao Chen _{2,

7} , Yi Ting Zhou _{1,

2,

7}

Affiliation

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. Stem Cells 2018;36:527–539

中文翻译：

AKT-mTOR 信号传导的激活指导间充质干细胞的肌腱发生

由于对肌腱发生的了解有限，肌腱修复是一项临床挑战。I 型胶原蛋白 (Collagen I) 和其他细胞外基质的合成对于肌腱分化和体内平衡至关重要。目前关于腱发生的研究主要集中在腱发生转录因子上，而在翻译水平上控制腱发生的信号传导仍然很大程度上未知。在这里，我们发现雷帕霉素 (mTOR) 信号传导的机制靶点被促蛋白生长因子、转化生长因子 beta1 和胰岛素样生长因子-I 激活。mTOR 的表达在间充质干细胞 (MSCs) 的腱发生过程中上调。此外，mTOR 在人肌腱病组织中下调，并在他汀类药物治疗后失活。AKT 或 mTOR 的抑制和消耗都显着减少了 I 型胶原蛋白的产生并损害了 MSCs 的肌腱形成。mTOR 的肌腱特异性消融导致肌腱缺损和胶原蛋白 I 减少。然而，在转录水平上没有明显的肌腱相关胶原蛋白下调。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新的治疗靶点。干细胞 2018；36：527–539 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新的治疗靶点。干细胞 2018；36：527–539 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新的治疗靶点。干细胞 2018；36：527–539

更新日期：2018-01-05

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