Activation of AKT-mTOR Signaling Directs Tenogenesis of Mesenchymal Stem Cells.
Xiao Xia CongXi Sheng RaoJun Xin LinXiao Ceng LiuGuang An ZhangXiu Kui GaoMin Yi HeWei Liang ShenWei FanDominique PiolettiLi Ling ZhengHuan Huan LiuHongwei OuyangBoon Chuan LowRonen SchweitzerHongwei OuyangXiao ChenYi Ting ZhouPublished in: Stem cells (Dayton, Ohio) (2018)
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.
Keyphrases
- cell proliferation
- rotator cuff
- mesenchymal stem cells
- anterior cruciate ligament reconstruction
- growth factor
- stem cells
- extracellular matrix
- umbilical cord
- signaling pathway
- poor prognosis
- gene expression
- endothelial cells
- cardiovascular disease
- transcription factor
- wound healing
- coronary artery disease
- tissue engineering
- case control