心脏Telocyte在心脏衰老和再生能力下降中的作用及其机制研究

Increase of Cardiac fibrosis and Decrease of number and function of cardiac stem cells are critical phenotypes of heart aging. Revealing of the molecular mechanism and the interventional strategy regarding to above aging phenotypes are crucial issue for us to demonstrate molecular mechanism of heart aging and delay heart aging. The up-to-date studies document that the renewal of cardiac myocyte is decreased during heart aging. Recently, we reported firstly that a novel interstitial cell, named as cardiac telocytes (CTs), is able to decrease infarct size and cardiac fibrosis in myocardial infarction (MI). Further studies also reveal that CTs are able to promote the proliferation of cardiac myocytes in border zone and survival of cardiac stem cells in hypoxia via miRNAs included in CTs secreted exosomes. The findings propose that CT aging might play an important role in deduction of renewal of cardiac myocytes and activation & survival of cardiac stem cells, and increase of cardiac fibrosis included in heart aging. The proposed project was therefore designed to investigate the molecular mechanism of CT aging, and its effects in above aging phenotypes in order to reveal novel molecular mechanism for heart aging. The results of present study will establish the novel molecular mechanism, targeting and interventional methodology for delay of dysfunction of cardiac myoctyes renewal, cardiac stem cell activation and survival, and improvement of cardiac fibrosis and regeneration of MI.

心肌层纤维化增加和心脏干细胞数目与功能的下降是心脏衰老的重要表型。阐释上述衰老表型发生及干预的分子机理是阐明心脏衰老分子机理与延缓心脏衰老急需解决的难题。最新研究表明心脏衰老伴随心肌细胞自我更新功能下降。我们最近率先报道：存在于心肌层的间质细胞--心脏Telocytes（CTs）有减小梗死心肌面积及心肌纤维化的疗效；进一步研究证明：CTs能促进缺血边缘区心肌细胞增殖及通过其分泌的外泌体miRNAs促进心脏干细胞在缺氧环境的存活。这些研究提示：CTs衰老在心脏衰老的心肌细胞自我更新、心脏干细胞激活与存活下降及心肌层纤维化增加的发生充当重要调控功能。本项目将对CTs衰老分子机理，及CTs衰老对上述心脏衰老重要表型发生的分子机理进行研究，揭示心脏衰老新的分子机理，为延缓随增龄心肌细胞自我更新、心脏干细胞激活与存活下降、心肌层纤维化增加、及心脏再生能力下降等心脏衰老表型带来新的分子机理及干预方法。

揭示了：心脏Telocyte（CTs）对心脏功能，及衰老表型，与其在缺氧环境表型改变等，对心脏衰老、结构功能退行性改变及再生潜能下降的调控通路和彼此作用的网络。并在此基础上重点阐释：①CTs通过分泌外泌体（CT-exos）作用于心脏构成细胞（心脏微血管内皮细胞，心脏成纤维细胞等），年青CTs通过其分泌CT-exos中含量第一的miR-21-5p，使用CT-exos-miR-21-5p-Cdip1-caspase3通路维持心脏微血管内皮细胞的存活与对抗凋亡，从而有效维持心脏血管新生功能及具有治疗缺血性心肌梗死疗效及相应机理；② CTs衰老，使年老CTs使用CT-exos-miRNA-486(含量第一)-SRSF3通路，促进心脏成纤维细胞和肌成纤维细胞的衰老、凋亡、及减少炎症反应、改善年老心脏纤维化和心室不良重构，及具有治疗缺血性心肌梗死疗效及相应机理；③对年老心脏使用年青CT-exos干预治疗，能有效改善心脏老化及其作用的机理；④对心梗心脏实施中等强度的运动，能有效改善梗死心脏死亡CTs的再生，有利于梗死心肌的修复与再生；⑤CTs可能通过其外泌体的miR-204-5p参与调控心脏微血管内皮细胞的BDNF全长型受体TrkB-FL表达下调，从而作用于年老心脏BDNF-TrkB通路促血管新生功能失能⑥建立使用成体热带爪蛙心脏再生模型及基因修饰技术，及其它有效干预心脏老化与再生的手段，并用于揭示心脏衰老、退行性变及有效再生心肌的新机理，研发出使用CTs改善心梗与心脏退行性改变的细胞制剂，获发明专利一件，研发出具基于CDIP1保护血管内皮细胞凋亡的方法，及靶向治疗心梗新方法已分别申请发明专利。项目成果为阐释心脏衰老，结构与功能性退行性变，及有效修复与再生梗死心肌带来基于CTs的作用机制、干预靶点及新疗法。已发表标注项目号文章13篇，获发明专利一项，申请二项。培养硕博士及博士后共7人。