Cell autonomous TGFβ signaling is essential for stem/progenitor cell recruitment into degenerative tendons

Summary Understanding cell recruitment in damaged tendons is critical for improvements in regenerative therapy. We recently reported that targeted disruption of transforming growth factor beta (TGFβ) type II receptor in the tendon cell lineage (Tgfbr2ScxCre) resulted in resident tenocyte dedifferentiation and tendon deterioration in postnatal stages. Here we extend the analysis and identify direct recruitment of stem/progenitor cells into the degenerative mutant tendons. Cre-mediated lineage tracing indicates that these cells are not derived from tendon-ensheathing tissues or from a Scleraxis-expressing lineage, and they turned on tendon markers only upon entering the mutant tendons. Through immunohistochemistry and inducible gene deletion, we further find that the recruited cells originated from a Sox9-expressing lineage and their recruitment was dependent on cell autonomous TGFβ signaling. The cells identified in this study thus differ from previous reports of cell recruitment into injured tendons and suggest a critical role for TGFβ signaling in cell recruitment, providing insights that may support improvements in tendon repair.

Graphical abstract

Highlights • Targeted deletion of TGFβ signaling led to degenerative changes in mouse tendons • Stem/progenitor cells were recruited into the degenerative mutant tendons • The recruited cells are different from the ones so far reported in tendon injury • Recruitment was dependent on cell autonomous TGFβ signaling in the recruited cells

In this article, Schweitzer and colleagues identify the recruitment of a new population of stem/progenitors into degenerative mutant mouse tendons and demonstrate that their recruitment was dependent on cell autonomous TGFβ signaling. This provides an opportunity to directly examine the origin of tendon stem/progenitor cells and the mechanisms of their activation, which is critical for improvement in tendon repair.