Regulation of Axin2-expressing cells in the adult tendon

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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.