Cell autonomous TGF-beta signaling is essential for cell recruitment into degenerating tendons

Understanding the role of cell recruitment in tendon disorders is critical for improvements in regenerative therapy. We recently reported that targeted disruption of TGF{beta} type II receptor in the tendon cell lineage (Tgfbr2ScxCre) resulted in tenocyte dedifferentiation and tendon degradation in post-natal stages. Here we extend the analysis and identify direct recruitment of stem/progenitor cells into the degenerative mutant tendons. Cre-lineage tracing indicates that these cells are not derived from tendon ensheathing tissues or from a Scleraxis-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 TGF{beta} signaling. These results thus differ from previous reports of cell recruitment into injured tendons, and suggest a critical role for TGF{beta} signaling and cell recruitment in the etiology and treatment of tendon degeneration.