Therapeutic inhibition of the Wnt signaling pathway to promote regenerative repair of tissue injury

Abstract

The Wnt/Beta-catenin pathway is an evolutionarily conserved pathway whose role in regeneration of mammalian tissue injury is incompletely understood. The pathway is quiescent in most mammalian organs and is reactivated in response to injury. Despite its role in stem cell self-renewal and homeostasis in many mammalian tissues, a substantial body of literature in a wide variety of mammalian tissue injury models points to a pro-fibrotic effect of Wnt pathway activation. With evidence supporting these distinct effects of Wnt signaling in adult organs, particularly derived from studies using genetic models of Wnt pathway modulation, we sought to investigate the effect of pharmacologic Wnt inhibition in two distinct injury models: the myocardial ischemic injury model and full-thickness skin injury model. Using newly available small molecule inhibitor of Wnt ligand secretion, we found that short term Wnt inhibition promoted recovery of cardiac function, reduced infarct size and prevented adverse remodeling in the infarcted heart. An investigation into the cellular mediators of this improved cardiac recovery showed that Wnt pathway inhibition promoted proliferation of cardiac progenitors, a subset of which were likely myogenic progenitors, reduced apoptosis of cardiomyocytes, prevented proliferation and collagen expression by myofibroblasts. Topical Wnt pathway inhibition in skin injury model showed an acceleration of ear punch wound closure, a reduction in fibrosis, and regeneration of skin adnexa and auricular cartilage. Our data using mechanistically distinct Wnt inhibitors in two very different injury models, add to the growing body of data indicating the potential of pharmacologic Wnt inhibition to achieve optimal healing outcome in mammalian injury in multiple organs including, lung, kidney and liver. As novel Wnt inhibitors with proven safety and efficacy progress through clinical studies, the development of Wnt inhibitory therapeutics for promoting regenerative injury repair becomes an exciting frontier.