Identification of a latent resident progenitor population in the adult tendon

Tendons connect and transfer force between the muscles and bones of the body, making them highly prone to injury. These injuries have imperfect healing, resulting in scarring and reduced mobility. Progress in the tendon field has been limited by a lack of markers to identify tendon progenitor cells in vivo. In our study, we first sought to determine the cell turnover rates during growth, homeostasis and injury using unique systems. We found higher proliferation rates during postnatal stages prior to 1 month of age, and significantly lower turnover rates after 1 month of age, which indicate a transition from cell growth to physiological homeostasis. By combining the TetO-H2B-GFP pulse-chase method with Axin2-CreErt2 labeling, we found that 10% of the adult tendon cells were labeled by Axin2 and that this distinct subset were latent slowly cycling cells. Axin2+ cells in culture were enriched for tendon genes and had higher proliferation rates compared with Axin2- cells. Lineage tracing experiments in an Achilles tendon injury model showed that Axin2+ cells were the predominant cell population at the healed site. Deletion of Porcupine, a factor necessary for Wnt secretion, in Scx-lineage cells resulted in impaired healing. Surprisingly, Axin2-CreERt2 deletion of Porcupine resulted in a similarly disrupted healing response with significantly decreased proliferation, gene expression, and Axin2+ cell infiltration. These data suggest that Axin2+ cells initiate their own healing response through autocrine signaling mechanisms. Our work identifies Axin2+ cells as a unique progenitor cell type in the adult tendon that are crucial to tendon healing.