Matricellular protein CCNN1 and EPC-mediated cardiac neovascularization

Myocardial neovascularization is critical for cardiac regeneration and functional restoration. CCN1, a secreted matricellular protein, has been shown to be a potent proangiogenic molecule and play an essential role in cardiovascular development. Evidence suggests that CCN1 can interact with different cell types through different domain structures in a tissue context dependent manner. Notably, CCN1 expression is strongly induced in the infarcted myocardium in mice, and in patients with ischemic cardiomyopathy, the levels of the CCN1 protein in the heart are in close correlation with the disease stages. However, the functional significance of CCN1 in the pathogenesis of ischemic heart disease is still largely unknown. Recently, we have reported that CCN1 markedly promotes migration and chemokine section of endothelial progenitor cells (EPCs) and appears to be an essential component of the microenvironment that guide the homing and engraftment of the transplanted EPCs in the injured vessels. Our follow up investigation reveal that CCN1 can bind to several subsets of bone marrow (BM) cells with both angiogenic and anti-angiogentic activities. The goal of this grant is to understand the functional significance of CCN1 in the ischemic cardiac repair and the underlying molecular and cellular mechanisms. The central hypothesis is that CCN1, produced in the ischemic myocardium, promotes cardiac repair by enhancing EPC homing, and that genetic engineering of specific domain structures of CCN1 can further improve tissue repair by specifically enhancing EPC homing. We will test our hypothesis with two specific aims. Aim 1 will confirm the role of CCN1 in the homing of BM-derived cells to the ischemic myocardium and the impact on heart functional recovery post-MI. Aim 2 will identify specific domain structures on CCN1 that can selectively promote the homing of EPCs for ischemic myocardium repair.