A latent stem cell pool is the central organizer of tendon healing

Tendons connect and transfer force between the muscles and bones of the body, making them highly prone to injury. These injuries encompass 30-50% of all sport and work-related injuries, have slow and imperfect healing with limited treatment options and result in scarring and reduced mobility. To impact regenerative biology approaches to a tendon injury and age-related tissue degeneration, it is essential to identify the cell types and pathways responsible for tendon repair mechanisms.

In our study, we revealed for the first time, a unique Axin2+ cell population embedded within the dense collagen matrix of tendons. We discovered, in adult mice, that the Axin2+ population, was slowly dividing in the tendon, however, upon culturing, the Axin2+ cells expressed known progenitor/stem cell markers and were expanded rapidly in vitro. After Achilles’ tendon injury, these Axin2+ cells proliferated, infiltrated to the wound site, differentiate into tendon cells, and were the major cellular contributors to tendon healing. Interestingly, specific loss of Wnt secretion via deletion of Porcupine (Porcn) in the adult Axin2+ population altered baseline gene expression of these cells and severely compromised the healing response after injury. We also found that Wnt9a is upregulated in the Axin2+ cells after injury. Remarkably, we discovered that Wnt9a and Axin2 expression depends upon autocrine Wnt secretion. Our work identifies for the first-time quiescent tendon stem cell population within the tendon and its rich matrix and provides a unique paradigm in stem cell niches, in which cells embedded within a dense connective tissue serve as their own niche.