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  2. Cystic fibrosis transmembrane conductance regulator mediates tenogenic differentiation of tendon-derived stem cells and tendon repair: accelerating tendon injury healing by intervening in its downstream signaling

Cystic fibrosis transmembrane conductance regulator mediates tenogenic differentiation of tendon-derived stem cells and tendon repair: accelerating tendon injury healing by intervening in its downstream signaling

  • FASEB J. 2017 Sep;31(9):3800-3815. doi: 10.1096/fj.201601181R.
Yang Liu 1 Jia Xu 2 Liangliang Xu 1 3 Tianyi Wu 1 2 Yuxin Sun 1 Yuk-Wai Lee 1 Bin Wang 1 Hsiao-Chang Chan 4 Xiaohua Jiang 4 Jinfang Zhang 5 6 Gang Li 7 6 8 9
Affiliations

Affiliations

  • 1 Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, China.
  • 2 Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 3 Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 4 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, China.
  • 5 Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, China; zhangjf06@gmail.com.
  • 6 Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, China.
  • 7 Department of Orthopaedics and Traumatology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, China; gangli@cuhk.edu.hk.
  • 8 Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, China.
  • 9 The Chinese University of Hong Kong-China Astronaut Research and Training Center Space Medicine Centre on Health Maintenance of Musculoskeletal System, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
Abstract

Tendons are a mechanosensitive tissue, which enables them to transmit to bone forces that are derived from muscle. Patients with tendon injuries, such as tendinopathy or tendon rupture, were often observed with matrix degeneration, and the healing of tendon injuries remains a challenge as a result of the limited understanding of tendon biology. Our study demonstrates that the stretch-mediated activation channel, cystic fibrosis transmembrane conductance regulator (CFTR), was up-regulated in tendon-derived stem cells (TDSCs) during tenogenic differentiation under mechanical stretching. Tendon tissues in CFTR-dysfunctional DF508 mice exhibited irregular cell arrangement, uneven fibril diameter distribution, weak mechanical properties, and less matrix formation in a tendon defect model. Moreover, both tendon tissues and TDSCs isolated from DF508 mice showed significantly decreased levels of tendon markers, such as scleraxis, tenomodulin, Col1A1 (collagen type I α 1 chain), and decorin Furthermore, by RNA Sequencing analysis, we demonstrated that Wnt/β-catenin signaling was abnormally activated in TDSCs from DF508 mice, thereby further activating the pERK1/2 signaling pathway. Of most importance, we found that intervention in pERK1/2 signaling could promote tenogenic differentiation and tendon regeneration both in vitro and in vivo Taken together, our study demonstrates that CFTR plays an important role in tenogenic differentiation and tendon regeneration by inhibiting the β-catinin/pERK1/2 signaling pathway. The therapeutic strategy of intervening in the CFTR/β-catenin/pERK1/2 regulatory axis may be helpful for accelerating tendon injury healing, which has implications for tendon injury management.-Liu, Y., Xu, J., Xu, L., Wu, T., Sun, Y., Lee, Y.-W., Wang, B., Chan, H.-C., Jiang, X., Zhang, J., Li, G. Cystic fibrosis transmembrane conductance regulator mediates tenogenic differentiation of tendon-derived stem cells and tendon repair: accelerating tendon injury healing by intervening in its downstream signaling.

Keywords

CFTR; ERK1/2; β-catenin.

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