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

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 intendon-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 a 1 chain), and decorin. Furthermore, by RNA sequencing analysis, we demonstrated that Wnt/beta-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 beta-catinin/pERK1/2 signaling pathway. The therapeutic strategy of intervening in the CFTR/beta-catenin/pERK1/2 regulatory axis may be helpful for accelerating tendon injury healing, which has implications for tendon injury management.