Abstract 3747: Endothelial Specific Inactivation of CXCR4 Receptor in Adult Mice Reveals the Pivotal Role of SDF-1/CXCR4 Axis in the Development of Endothelial Progenitor Cells (EPCs) for Myocardiac Infarction

Abstract

The development of endothelial progenitor cells (EPCs) is markedly modulated by vascular niche-derived factors for maintaining EPC pool in adult bone marrow. Although SDF-1a/CXCR4 axis have shown to play a critical role in maintaining hematopoietic stem cell (HSC) pool, the precise regulatory mechanism of EPC development remain unclear. In the analysis of tie-2 specific inactivation of CXCR4 in adult mice, we have found that the number of CD34(−/low)/c-kit(+)/Sca-1(+)/Lin(−) or side population (SP) stem cells is profoundly increased. In addition, EPC colony forming capacity of CD34(−)/c-kit(+)/Sca-1(+)/Lin(−) stem cells in endothelial specific CXCR4 null mice are drastically enhanced. Notably, the development of definitive EPC, a late stage of EPC development, is specifically impaired in Tie2cre-CXCR4 null mice, although the colony number of primitive EPCs, an early stage of EPC development, is profoundly increased. EPCs derived from endothelial specific CXCR4 null mice showed showed immatured EPC function, such as migration capacity, proliferation, cell survival. When cultured with SDF-1, niche-derived stem cells gave rise to promoted EPC colony forming capacity. In myocardiac infarction model, we observed the significantly reduced cardiac function,when measured by echocardiography. Furthermore, capillary density was also significantly decreased, as well as induced fibrosis in endothelial specific CXCR4 null mice. In conclusion, the present report clearly showed for the first time that the SDF-1a/CXCR4 axis plays a pivotal role in EPC maturation in special niche, suggesting that the full understanding of EPC development via regulating SDF-1-CXCR4 axis provide a key source of therapeutic tissue regeneration.