A latent Axin2/Scx progenitor pool is the central organizer of tendon healing.

A tendon's ordered extracellular matrix (ECM) is essential for transmitting force but is also highly prone to injury. How tendon cells embedded within and surrounding this dense ECM orchestrate healing is not well understood. Here, we identify a specialized quiescent Scx/Axin2 population in mouse and human tendons that initiates healing and is a major functional contributor to repair. Axin2 cells express stem cell markers, expand in vitro, and have multilineage differentiation potential. Following tendon injury, Axin2-descendants infiltrate the injury site, proliferate, and differentiate into tenocytes. Transplantation assays of Axin2-labeled cells into injured tendons reveal their dual capacity to significantly proliferate and differentiate yet retain their Axin2 identity. Specific loss of Wnt secretion in Axin2 or Scx cells disrupts their ability to respond to injury, severely compromising healing. Our work highlights an unusual paradigm, wherein specialized Axin2/Scx cells rely on self-regulation to maintain their identity as key organizers of tissue healing.