A quiescent resident progenitor pool is the central organizer of tendon healing

Abstract

A tendons ordered extracellular matrix (ECM) is integral for transmitting force and highly prone to injury. How tendon cells, or tenocytes, embedded within this dense ECM mobilize and contribute to healing is unknown. Here, we identify a specialized Axin2+ population in mouse and human tendons that remains latent in homeostasis yet initiates the healing response and serves as a major source of tendon progenitors. Axin2+ tenocytes readily expand in vitro and express stem cell markers. In vivo, Axin2+-descendants are major functional contributors to repair: Axin2+ tenocytes proliferate, acquire injury responsive states, and re-adopt a tenocyte fate post-injury. Specific loss of Wnt secretion in Axin2+ cells alters their progenitor identity, disrupts their activation upon injury, and severely compromises any healing response. Our work highlights an unusual paradigm, wherein quiescent Axin2+ tenocytes self-regulate their identity and mobilization upon injury and provide the key initiating signal to organize a tendon-wide healing response.