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

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