整合素beta1在诱导性干细胞来源的血管内皮前体细胞参与血管新生中的作用

血管新生为损伤组织打开生命通道，血管新生障碍是许多伤病久治不愈的原因。诱导性多能干细胞（iPSC）应用潜力巨大，但迫切需要更安全有效可控的应用策略。申请人发现：分化为血管内皮细胞（ECs）并促血管新生是自体和异体iPSC促进猴和小鼠创面愈合的主要机制，但iPSC迁移距离有限；iPSC体外分化的早期内皮祖细胞（iPSC-EPC），失去多分化性，成为ECs定向分化细胞并促进损伤血管修复，但其仍表达整合素β1（ITGb1）并拥有迁移性和与ECs黏附的能力;ITGb1介导iPSCs与ECs、iPSCs与细胞外基质（ECM）粘附。拟进一步明确iPSC-EPC与ECM粘附对iPSC-EPC体内外存活、分化、迁移、定植锚定、血管新生和治疗作用的影响，以及ITGb1在其中的作用；ITGb1对iPSC-EPC跨血管迁移和血管新生的作用。为安全高效可控应用iPSC及其衍生细胞提供理论依据。

Angiogenesis is a most important process of wound healing and one of the most important mechanisms of stem cell therapy. Induced pluripotent stem cells (iPSC) have great potential in regenerative medicine but were abandoned in direct in vivo application due to their side effects such as capability of forming teratoma. Recently, investigators, including the applicant, have developed strategies for preventing side effect of in vivo administered iPSC. Currently, an urgent need is to develop strategy that can significantly improve therapeutic function of iPSC while making the cells safer and more controllable. In monkey and mouse wound healing models, we found promoting angiogenesis and becoming endothelial cells were the major mechanism by which autologous and allogeneic iPSC promote skin wound healing. However, the interstitial distance an iPSC can migrate is limited. iPSC-derived endothelial progenitor cells (iPSC-EPC)lost their pluripotency and became endothelial linkage cells. Importantly, the capabilities of the cells to express integrin beta1 and adhering to and then migrating across endothelial monolayer remained. Preliminary experiment showed integrin using integrin beta-1 as beta unit was responsible for the adhesion between iPSC and extracellular matrix proteins (ECM), and between iPSC and endothelial cells. This project will further demonstrates the effect of interaction between iPSC-EPC and ECM interaction on iPSC-EPC extravasation, migration, immobilization, survival, proliferation, differentiation, therapeutic function and iPSC-EPC promoted angiogenesis, and the roles of integrin beta-1 in vivo and in vitro. Similar experiments will be performed to determine the role of integrin beta-1 on the interaction of iPSC-EPC and EC. Our result will have great impact on reviving the valuable application of iPSC-EPC in vivo.