应用AT2受体阳性骨髓干细胞亚群有效改善心肌修复

Clinical trials have shown that the therapeutic efficiency of autologous transplantation of bone marrow (BM) stem/progenitor cells for ischemic cardiomyopathy remains low. There is an urgent need in the clinical settings to enhance therapeutic potentials of autologous transplantation of stem/progenitor cells derived from patients with ischemic cardiomyopathy. Angiotensin II, interferes with cardiac repair mechanisms, via its AT1 and AT2 receptor (R). Little is known about AT2R-mediated cellular mechanisms in the heart. We have recently defined the BM CD117+AT2R+ cell population, which increases and mediates cardiac repair in response to acute myocardial infarction in rats. In this translational project, we hypothesize that the application of human BM CD117+AT2R+ cells in combination with preconditioning via AT2R activation may potentially offer new translational options to improve therapeutic efficiency of BM stem/progenitor cells derived from patients with ischemic cardiomyopathy. The main aims of the project are to characterize and explore the regenerative potentials of BM CD117+AT2R+ cells derived from patients with ischemic cardiopathy, and to further study their therapeutic efficiency upon modification via AT2R stimulation in myocardial infarction models of immunodeficient (SCID) mice (proof of concept).

临床试验显示骨髓干细胞移植治疗缺血性心肌病的疗效并不理想。探索合适的骨髓干细胞亚群及增强病人来源骨髓干细胞功效的干预措施，是提高骨髓干细胞临床疗效的迫切需求。血管紧张素II通过其AT1和AT2受体（AT2R）参与心肌损伤修复机制。对于AT2R介导的功能目前了解甚少。我们前期研究发现能向受损心肌选择性迁移并促进心肌修复的骨髓CD117+AT2R+干细胞亚群。本项目将深入探讨是否通过应用CD117+AT2R+干细胞亚群及激活AT2受体的干预措施能有效地增强病人来源骨髓干细胞治疗缺血性心肌病的疗效。研究内容包括系统分析缺血性心肌病人骨髓CD117+AT2R+（vs. CD117+AT2R-）细胞的自我更新，迁移及分化潜质和功能；通过小鼠（SCID）心梗模型体内评估验证应用病人骨髓CD117+AT2R+干细胞亚群结合激活AT2受体的干预措施改善心肌修复的有效性和临床可行性。

本项目的研究内容包括：特征性分析AT2受体阳性细胞亚群的独特自我更新，迁移及分化潜质和功能; 通过动物心梗模型体内评估验证应用AT2受体阳性细胞亚群结合激活AT2受体的干预措施改善心肌修复的有效性和临床转化可行性。.本项目的研究结果证实来源于缺血心肌损伤鼠模型和临床病人的AT2受体阳性骨髓干细胞的干性特征及迁移能力均优于AT2受体阴性骨髓干细胞。同时发现两种能有效抑制炎症心血管损伤的新型T细胞亚群。研究结果表明通过活化AT2R受体结合应用人心血管组织脱细胞基质材料的创新干预措施可明显增强骨髓干细胞的治疗心血管损伤的疗效，具有重要的临床转化潜力和市场开发前景。主要创新点包括：.（1）.骨髓AT2受体阳性干细胞亚群的干性明显优于AT2受体阴性干细胞亚群。.（2）.活化AT2受体能促进骨髓干细胞向缺血损伤心肌迁移，向心肌分化及其修复心肌的能力。.（3）.发现包括AT2受体阳性T细胞在内的能有效抑制炎症心血管损伤的两种新型T细胞亚群。.（4）.基于病人心血管组织脱细胞基质材料，建立一整套新型心肌组织工程方法提高（AT2受体阳性）骨髓干细胞治疗心血管损伤的疗效。