SDF-1α-CXCR7-Rac1/VEGF协同诱导内皮祖细胞血管新生在脑卒中神经康复中的机制研究

Ischemic stroke is the common and severe disease with mostly secondary neural dysfunction. Endothelial progenitor cells (EPCs) are key cell resources during tube formation and neovascularization of ischemic tissues through cell proliferation and migration. Thus, transplantation of EPCs has been widely applied in treatment of vessel-related diseases. Vascular endothelial growth factor (VEGF) is a very important factor in recruitment and rearrangement of endothelial progenitor cells (EPCs) for angiogenesis. Our preliminary study also indicated that stromal-derived factor-1 (SDF-1α) mediates endothelial cell migration and directional tube formation through new receptor CXCR7 and Rho family RAC1 signaling. But the underlying mechanisms are not clear. In this study, we will investigate that SDF-1α and VEGF might act synergistically on EPC-derived angiogenesis though SDF-1α/CXCR7/Rac1 signaling pathway. In addition, we also will explore an effective cell transplantation strategy to promote neural repair and clinical neural rehabilitation in ischemic stroke.

缺血性卒中是严重危害人类健康的疾病之一，大部分患者遗留神经功能缺陷，如何促进血管神经功能重建是治疗的关键。自体移植内皮祖细胞（EPC）因可通过增殖、定向迁移，参与缺血区血管新生、促进神经功能康复受到广泛关注。研究发现，脑卒中缺血区SDF-1α和VEGF的表达水平上调，并且促进外源性EPC参与管腔形成，但具体机制不明。本研究的前期结果已证实SDF-1α新型CXCR7受体在内皮细胞管腔形成的过程中的重要作用，相关研究也证实SDF-1α/CXCR7可能具有独立的信号通路，通过激活Rac1促进神经干细胞的极化和迁移。因此我们假设在缺血性卒中后，上调的SDF-1α活化CXCR7，与VEGF协同激活Rac1，诱导EPC管腔形成，促进血管定向新生及神经功能修复。本项目将通过体内外实验，探索SDF-1α和VEGF协同作用的分子机制，并探索这些重要因子促进神经修复的时机和条件，具有重要的临床意义和创新性。

缺血性中风后，神经损伤的修复需要新生血管为其提供营养。我们通过研究内皮祖细胞（Endothelial progenitor cell，EPC）在血管新生过程中，VEGF(血管内皮生长因子)与SDF-1α-CXCR7联合作用，改善EPC的增殖迁移与管腔形成。提取人脐静脉内的EPC,通过条带实验和管腔形成实验分别证明VEGF与SDF-1α联合能够更强的诱导EPC伸出伪足并促进其迁移和管腔形成，并且两者联合能够使EPC更多的表达CXCR7。EPC本身具有很强的促进增殖作用，两者联合对于EPC的促进增殖作用并不明显。血管新生后，在神经修复中我们同样探讨了内皮细胞（endothelial cell，EC）所发挥的作用。提取EC的外泌体，发现能够促进神经干细胞的增殖、迁移和抗凋亡作用。并且我们通过脑立体定位注射EC外泌体，发现无论是行为还是MRI，都较模型组出现了明显改善。