TGFβ signaling is required for tenocyte recruitment and functional neonatal tendon regeneration

Abstract

Tendon injuries are common with poor healing potential. The paucity of therapies for tendon is due to our limited understanding of the cells and molecules that drive tendon regeneration. Using a model of neonatal mouse tendon regeneration, we determined the molecular basis for regeneration and identify TGF{beta} signaling as a major pathway. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGF{beta}-dependent and -independent mechanisms underyling tendon regeneration. Importantly, functional recovery depended on TGF{beta} signaling and loss of function is due to impaired tenogenic cell recruitment from both Scxlin and non-Scxlin sources. We show that TGF{beta} signaling is required directly in neonatal tenocytes for recruitment and that TGF{beta} is positively regulated in tendons. Collectively, these results are the first to show a functional role for TGF{beta} signaling in tendon regeneration and offer new insights toward the divergent cellular activities that may lead to regenerative vs fibrotic healing.