FST在心血管前体细胞治疗小鼠急性心肌梗死中的作用和机制

Stem cell transplantation has been a prospective method for the treatment of acute myocardial infarction (AMI), but the appropriate transplanted cell types and the related mechanism are still poorly understood. Our recent studies demonstrated that the transplantation of human embryonic stem cell-derived cardiovascular progenitor cells (hCVPCs) significantly improved AMI by improving post-AMI cardiac functiion, limiting fibrous scar and inhibiting inflammation in AMI hearts. Moreover, we detected a high level of cell factor follistatin (FST) in the hCVPC culture media. We further found that it attenuated oxidative stress-induced cell death, promoted angiogenesis, and stimulated the transformation of macrophage from M1 to M2 in vitro. We thus raise the following hypothesis: FST may improve myocardial injury and cardiac repair after AMI through the modulation of inflammatory responses. To test it, this project aims to explore the following questions: 1) if FST is effective in the AMI treatment? 2) what is the role of FST in the inflammatory response during AMI and its contribution to the therapeutic effect of hCVPCs transplantation in the AMI? 3) How does FST regulate the inflammatory response in AMI with and without hCVPCs transplantation? The results will provide the insight into the knowledge of the paracrine effects of hCVPCs and the mechanism involved in the inflammatory regulation of AMI and will also provide the experimental evidence for the clinical study of AMI treatment.

干细胞移植已有可能成为有效治疗心肌梗死的新方法，但对适宜的移植细胞种类及其作用机制还有待进一步的研究。我们近期工作发现移植人胚胎干细胞源心血管前体细胞（hCVPCs）明显改善急性心肌梗死（AMI）后心功能，减小心梗面积，抑制AMI后的炎症反应；并发现hCVPCs分泌大量的细胞因子卵泡抑素（FST）；进一步研究证明FST可改善氧化应激损伤后的细胞存活率、促进血管形成及巨噬细胞M1型向M2型转化。因此我们提出如下假说：FST可通过调控炎症反应改善AMI后的心肌细胞损伤和修复。为验证此假说，本项目拟探讨如下问题：1）FST是否有效治疗急性心梗？2）FST对心梗区炎症反应的作用及其在hCVPCs治疗AMI中的贡献？3）FST通过调控炎症反应参与hCVPCS治疗AMI的机制？其研究发现将丰富对hCVPCs旁分泌作用和对AMI炎症反应调控机制的认识，为心梗治疗的临床实践提供依据。