Abstract 402: Endothelial Specific Jagged-1/Notch Signal in Bone Marrow Niche Regulates Endothelial Progenitor Cell Development
The developmental cascade of endothelial progenitor cells (EPCs) in response to environmental signals is dynamically regulated by tight-communication between stem cells and stromal cells in bone marrow niches. We have recently reported that Jagged-1 dependent signals specifically regulated EPC-mediated vascularization using mice of Mx-cre dependent inactivation of jagged-1. However, the specific contribution of EPC development via modulating endothelial Jagged-1/Notch axis remain unclear. EPC colony forming capacity of CD34(−)/c-kit(+)/Sca-1(+)/Lin(−) stem cells in tamoxifen-treated Tie2cre-Jagged-1 null mice are drastically enhanced, although the CFU-EPC in CD34(+)/c-kit(+)/Sca-1(+)/Lin(−) progenitor cells was significantly impaired in Jagged-1 null mice. Moreover, the impaired EPC development was also confirmed in single cell-derived EPC colony forming assay. Notably, the development of primitive EPC, an early stage of EPC development, was significantly increased in stem cells, while progenitors derived from BM niche did not give rise to form definitive EPC, a late stage of EPC development. Similarly, we observed markedly decreased cell number and CFU-EPC of progenitor subset (Sca-1+/c-Kit+) in cultured EPCs. Isolated Jag-1 deficient progenitors in cultured EPCs never gave rise to definitive EPC, while WT-derived progenitor did. When co-culture with stromal cells derived from endothelial specific Jagged-1 null mice, stem cells could not develop functional EPCs. EPCs from endothelial specific Jagged-1 deficient niche showed impaired in vitro migration capacity in response to VEGF, SDF-1a, SCF or TPO, as well as the decreased incorporation ability into ischemic neo-vessel. In hind limb ischemia models, we observed the significantly reduced blood vessel regeneration with the decreased capillary density in endothelial specific Jagged-1 null mice. In conclusion, the present report clearly showed for the first time that the Jagged-1/Notch axis plays a pivotal role in EPC development in special niche, suggesting that modulation of EPC development via regulating Jagged-1/Notch axis provide a clue of therapeutic tissue regeneration.