人羊膜干细胞在心肌再生和重构中的作用及其分子机制

Ischemic heart disease is a major cause of death in the world. It is important to regenerate the injured heart and prevent myocardial remodeling after ischemia. Human amniotic stem cell transplantation has been shown to decrease infarction size and improve heart functions in ischemic animals, but the mechanism is unknown. In preliminary studies, we observed that human amniotic stem cells expressed many embryonic stem cell markers and their conditioned medium could significantly inhibit human cardiac fibroblast differentiation into myofibroblasts induced by TGF-β1. Therefore, we hypothesize that amniotic stem cells can not only differentiate into cardiomyocytes, but also exert paracrine anti-fibrotic effects through regulation of cardiac fibroblast. To test this hypothesis, in this project we will study the potentials of two types of amniotic stem cells to differentiate into “mature cardiomyocyte” and their effects on cardiac fibroblast differentiaiton in vitro. We will also treat the mice with acute myocardial infarction by human amniotic stem cell transplantation, and study the effects of the transplantaiton on heart functions and structural remodeling as well as on TGF-β1/Smads and TRPM7/Ca2+ signaling pathways in the heart. Therefore, the goal of this project is to evaluate the regeneration and anti-remodeling functions of human amniotic stem cells and to study the underlying molecular mechanisms, which may identify new therapeutic targets for ischemic heart disease treatment.

缺血性心脏病是世界范围内主要致死性疾病。促进缺血后心肌再生和延缓心肌重构成为临床治疗的关键。已有研究证实，人羊膜干细胞移植能够减少心肌缺血动物梗死面积和改善心功能，但具体机制尚未明确。我们在前期工作中发现，人羊膜干细胞表达多种胚胎干细胞标志物，其条件培养液能够显著抑制TGF-β1诱导的人类心肌成纤维细胞向肌纤维母细胞的分化。由此我们推测，人羊膜干细胞除了具有向心肌细胞分化潜能外，还可能通过其旁分泌作用调控心肌成纤维细胞来抑制心肌纤维化的形成，参与心肌逆重构。本项目拟通过体外观察两种人羊膜干细胞向“成熟心肌”分化的潜能以及对心肌成纤维细胞生物学功能的影响；在体观察移植人羊膜干细胞对急性心肌梗死小鼠的心功能和结构重建、以及对TGF-β1/Smads、TRPM7/ Ca2+信号通路的影响，探讨人羊膜干细胞在缺血后心肌再生和重构中的作用及其潜在的分子机制，为临床上缺血性心脏病的治疗提供新思路。

缺血性心脏病是世界范围内主要致死性疾病。促进缺血后心肌再生和延缓心肌重构成为临床治疗的关键。本研究结果显示：人羊膜干细胞表达多种胚胎干细胞标志物,具有多向分化潜能，其条件培养液能够显著抑制TGF-β1诱导的人类心肌成纤维细胞向肌纤维母细胞的分化。向急性心梗小鼠心肌损伤处移植人羊膜上皮干细胞，人羊膜间充质干细胞或其条件培养液混合物，能够显著减少心肌梗死面积和心肌纤维化的生产，提高心脏能力，其作用可能是通过羊膜干细胞的旁分泌作用调节心肌成纤维细胞上面的TRPM7通道蛋白活性，减少纤维化的生产。本研究进一步证明了移植人羊膜干细胞或其条件培养液有助于心肌梗死后的心肌修复过程，为临床上缺血性心脏病的治疗提供新思路。