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 TGFβ signaling as a major pathway. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGFβ-dependent and –independent mechanisms underyling tendon regeneration. Importantly, functional recovery depended on TGFβ signaling and loss of function is due to impaired tenogenic cell recruitment from both Scx lin and non- Scx lin sources. We show that TGFβ signaling is required directly in neonatal tenocytes for recruitment and that TGFβ is positively regulated in tendons. Collectively, these results are the first to show a functional role for TGFβ signaling in tendon regeneration and offer new insights toward the divergent cellular activities that may lead to regenerative vs fibrotic healing.