Rationale: Mesenchymal stromal cells (MSC)-based therapy is promising against ischemic heart failure (IHF). However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembrane protein capable of enhancing cell-cell adhesion, N-cadherin garnered attention in the field of stem cell biology only recently. Objective: The current study investigates whether and how N-cadherin may regulate MSC retention and cardioprotective capability against IHF. Methods and Results: Adult mice-derived adipose tissue-derived MSC (ADSC) were transfected with adenovirus harboring N-cadherin (ADSC-Ncad), T-cadherin (ADSC-Tcad), or control adenovirus (ADSC-con). CM-DiI-labeled ADSC were intramyocardially injected into the infarct border zone at 3 sites immediately after myocardial infarction (MI) or myocardial ischemia/reperfusion (MI/R). ADSC retention/survival, cardiomyocyte apoptosis/proliferation, capillary density, cardiac fibrosis, and cardiac function were determined. Discovery-driven/cause-effect analysis was employed to determine the molecular mechanisms. Compared to ADSC-con, N-cadherin overexpression (but not T-cadherin) markedly increased engrafted ADSC survival/retention up to 7 days post-MI. Histological analysis revealed that ADSC-Ncad significantly preserved capillary density and increased cardiomyocyte proliferation, and moderately reduced cardiomyocyte apoptosis 3 days post-MI. More importantly, ADSC-Ncad (but not ADSC-Tcad) significantly increased LVEF and reduced fibrosis in both MI and MI/R mice. In vitro experiments demonstrated that N-cadherin overexpression promoted ADSC-cardiomyocyte adhesion and ADSC migration, enhancing their capability to increase angiogenesis and cardiomyocyte proliferation. MMP-10/13 and/or HGF upregulation is responsible for N-cadherin's effect upon ADSC migration and paracrine angiogenesis. N-cadherin overexpression promotes cardiomyocyte proliferation by HGF release. Mechanistically, N-cadherin overexpression significantly increased N-cadherin/β-catenin complex formation and active β-catenin levels in the nucleus. β-catenin knockdown abolished N-cadherin overexpression induced MMP-10, MMP-13, and HGF expression, and blocked the cellular actions and cardioprotective effects of ADSC overexpressing N-cadherin. Conclusions: We demonstrate for the first time that N-cadherin overexpression enhances MSC protective effects against IHF via β-catenin mediated MMP-10/MMP-13/HGF expression and production, promoting ADSC/cardiomyocyte adhesion and ADSC retention.

中文翻译：

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N-钙黏着蛋白过表达动员间充质基质细胞通过依赖于Β-Catenin的方式来保护缺血性心脏病。

原理：基于间质基质细胞（MSC）的治疗有望治疗缺血性心力衰竭（IHF）。但是，由于细胞滞留率低和旁分泌功能差，其功效受到限制。N-钙粘着蛋白是一种能够增强细胞与细胞粘附的跨膜蛋白，直到最近才在干细胞生物学领域引起关注。目的：目前的研究探讨了N-钙粘蛋白是否以及如何调节MSC对IHF的保留和心脏保护能力。方法和结果：成年小鼠来源的脂肪组织来源的MSC（ADSC）被带有N-钙粘蛋白（ADSC-Ncad），T-钙粘蛋白（ADSC-Tcad）或对照腺病毒（ADSC-con）的腺病毒转染。心肌梗死（MI）或心肌缺血/再灌注（MI / R）后立即将CM-DiI标记的ADSC心肌内注射到3个部位的梗塞边界区域。确定了ADSC保留/存活，心肌细胞凋亡/增殖，毛细血管密度，心脏纤维化和心脏功能。发现驱动/因果分析用于确定分子机制。与ADSC-con相比，N-钙粘蛋白的过度表达（而非T-钙粘蛋白）显着增加了MI后7天的植入ADSC存活/保留率。组织学分析显示，MI后3天，ADSC-Ncad可显着保留毛细血管密度并增加心肌细胞增殖，并适度降低心肌细胞凋亡。更重要的是，在MI和MI / R小鼠中，ADSC-Ncad（而不是ADSC-Tcad）显着增加LVEF并减少纤维化。体外实验表明，N-钙黏着蛋白的过度表达促进了ADSC-心肌的粘附和ADSC迁移，增强其增加血管生成和心肌细胞增殖的能力。MMP-10 / 13和/或HGF上调负责N-钙粘蛋白对ADSC迁移和旁分泌血管生成的影响。N-钙黏着蛋白的过表达通过HGF的释放促进心肌细胞的增殖。从机理上讲，N-钙粘蛋白的过表达显着增加了核中N-钙粘蛋白/β-连环蛋白复合物的形成和活性β-连环蛋白的水平。β-catenin的敲除消除了N-钙粘蛋白的过表达诱导的MMP-10，MMP-13和HGF的表达，并阻断了ADSC过表达N-钙粘蛋白的细胞作用和心脏保护作用。结论：我们首次证明N-钙粘蛋白的过表达通过β-catenin介导的MMP-10 / MMP-13 / HGF的表达和产生来增强MSC对IHF的保护作用，