A significant portion of the population is affected by tendon injuries. Due to limited
regenerative potential, these injuries are complicated by slow and imperfect healing. In order to
develop therapies to improve healing outcomes, it is important to understand the mechanisms
regulating adult tendon cells during homeostasis and healing. Tendon-derived stem/progenitor
cells have been identified in vitro and display stem/progenitor characteristics, including
clonogenicity, multilineage differentiation potential, and self-renewal. However, the identity and
activity of resident progenitor populations in the adult tendon are not well understood. We have
identified an adult tendon cell marked by Axin2-CreERt2 that displays progenitor-like activities in
vitro and in vivo. After tendon injury, Axin2+ cells proliferate, infiltrate the injury site, and express
Scx-GFP. In addition, we find their injury response is dependent upon the Wnt pathway. We
propose to use lineage tracing, genetic loss of function, and next generation sequencing
techniques to gain a mechanistic understanding of Axin2+ cells in the adult tendon during
homeostasis and healing. We will test the hypothesis that Axin2+ cells are a unique tendon cell
population that, through Wnt secretion and response, are key orchestrators of tendon healing.
First, we will test the function of Wnt signaling in maintaining Axin2+ progenitor cell identity during
homeostasis. Next, we will define the function of Wnt secretion and canonical Wnt signaling in
regulating Axin2 cell injury response at early and later stages of tendon healing. We will also test
if activation of canonical Wnt signaling promotes Axin2+ cell identities and injury response,
leading to improved healing outcomes. A mechanistic understanding of Axin2+ cell function is an
integral step towards expanding our fundamental understanding of adult tendon biology. This
knowledge could impact the design of new therapies to improve tendon healing in patients.