Activation of AKT-mTOR Signaling Directs Tenogenesis of Mesenchymal Stem Cells. (5th January 2018)

• Record Type: Journal Article
• Authors: Cong, Xiao Xia; Rao, Xi Sheng; Lin, Jun Xin; Liu, Xiao Ceng; Zhang, Guang An; Gao, Xiu Kui; He, Min Yi; Shen, Wei Liang; Fan, Wei; Pioletti, Dominique; Zheng, Li Ling; Liu, Huan Huan; Yin, Zi; Low, Boon Chuan; Schweitzer, Ronen; Ouyang, Hongwei; Chen, Xiao; Zhou, Yi Ting
• Is Part Of: Stem cells. Volume 36:Number 4(2018)
• Page Start: 527
• Page End: 539
• Publication Date: 2018-01-05
• Subjects: Tendon -- Tenogenesis -- Mechanistic target of rapamycin -- AKT -- Type I collagen; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2765
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract : 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. Abstract : Current studies on tenogenesis have focused mostly on the tenogenic transcription factors including SCX, MKX, and EGR. These tenogenic transcription factors are upregulated by pro-tendon growth factors, such as TGF-β and IGF-1. Here, it was demonstrated that AKT-mTOR axis can be activated during tenogenesis. Knockout of mTOR resulted in tendon defects. This finding strongly supports that AKT-mTOR axis serves as a novel essential node for tenogenesis.