Abstract 20118: Wnt1 Mediated Dynamic Injury Response Activates the Epicardium and is Critical for Mammalian Cardiac Repair
The epicardium is activated following acute cardiac injury in zebrafish and plays a critical role in heart regeneration. The role of the mammalian epicardium in cardiac repair is unknown. The Wnt signaling system plays an important role in repair and regeneration in several organ systems. We investigated the role of Wnts in cardiac repair and demonstrate that a dynamic Wnt1 injury response activates the epicardium and regulates repair after ischemic injury. We initially screened for changes in expression of all 19 Wnts by qPCR in mouse hearts (C57/Bl6) following acute ischemia-reperfusion injury and observed a dramatic 8 fold increase in Wnt1 expression within the first two days of cardiac injury. In-situ hybridization to Wnt1 showed initial Wnt1 expression in the epicardium with migration of Wnt1 expression to the region of injury by 10 days. To corroborate our findings, we induced acute cardiac injury in Wnt1Cre/R26RlacZ mice and observed lac Z expression in the epicardium and cardiac fibroblasts in the region of injury. To demonstrate that the heart was Wnt responsive, we injured TOPGAL transgenic mice (Wnt reporter mice) and observed lacZ expression in the epicardium organ wide and region of injury consistent with the epicardium and cardiac fibroblasts being responsive to Wnt1 signaling. To track the fate of epicardial cells, we next induced cardiac injury in Wt-1(Wilms tumor)Cre/R26RlacZ and Col1a2Cre(ER)/R26Rlacz mice and observed progressive expansion of the epicardium that peaked at 7 days. Epicardial cells invaded into the subepicardial space and adjoining myocardium through myofascial planes, underwent EMT generating cardiac fibroblasts that expressed type 1 collagen. Using tamoxifen inducible Cre/lox techniques, we interrupted downstream Wnt/catenin signaling in cardiac fibroblasts and observed a dramatic phenotype of acute heart failure and death within the first few days of cardiac injury. These findings reveal a hitherto unrecognized role of a Wnt1 dynamic cardiac injury response that activates the epicardium and is critical for preservation of cardiac function and survival.
- © 2010 by American Heart Association, Inc.