Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G094J, Birmingham, AL 35294, USA.
Cardiovasc Res. 2020 Mar 1;116(3):671-685. doi: 10.1093/cvr/cvz179.
In regenerative medicine, cellular cardiomyoplasty is one of the promising options for treating myocardial infarction (MI); however, the efficacy of such treatment has shown to be limited due to poor survival and/or functional integration of implanted cells. Within the heart, the adhesion between cardiac myocytes (CMs) is mediated by N-cadherin (CDH2) and is critical for the heart to function as an electromechanical syncytium. In this study, we have investigated whether the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) can be enhanced through CDH2 overexpression.
CDH2-hiPSC-CMs and control wild-type (WT)-hiPSC-CMs were cultured in myogenic differentiation medium for 28 days. Using a mouse MI model, the cell survival/engraftment rate, infarct size, and cardiac functions were evaluated post-MI, at Day 7 or Day 28. In vitro, conduction velocities were significantly greater in CDH2-hiPSC-CMs than in WT-hiPSC-CMs. While, in vivo, measurements of cardiac functions: left ventricular (LV) ejection fraction, reduction in infarct size, and the cell engraftment rate were significantly higher in CDH2-hiPSC-CMs treated MI group than in WT-hiPSC-CMs treated MI group. Mechanistically, paracrine activation of ERK signal transduction pathway by CDH2-hiPSC-CMs, significantly induced neo-vasculogenesis, resulting in a higher survival of implanted cells.
Collectively, these data suggest that CDH2 overexpression enhances not only the survival/engraftment of cultured CDH2-hiPSC-CMs, but also the functional integration of these cells, consequently, the augmentation of the reparative properties of implanted CDH2-hiPSC-CMs in the failing hearts.
在再生医学中，细胞心肌成形术是治疗心肌梗死（MI）的有前途的选择之一；然而，由于植入细胞的存活率和/或功能整合较差，这种治疗的效果显示是有限的。在心脏内，心肌细胞（CMs）之间的黏附由 N-钙黏蛋白（CDH2）介导，对于心脏作为机电联体发挥功能至关重要。在这项研究中，我们研究了通过过表达 CDH2 是否可以增强人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）的修复潜力。
在肌生成分化培养基中培养 CDH2-hiPSC-CMs 和对照野生型（WT）-hiPSC-CMs 28 天。使用小鼠 MI 模型，在 MI 后第 7 天或第 28 天评估细胞存活率/植入率、梗死面积和心脏功能。在体外，CDH2-hiPSC-CMs 的传导速度明显快于 WT-hiPSC-CMs。而在体内，CDH2-hiPSC-CMs 治疗 MI 组的心脏功能测量值：左心室（LV）射血分数、梗死面积缩小和细胞植入率明显高于 WT-hiPSC-CMs 治疗 MI 组。在机制上，CDH2-hiPSC-CMs 通过旁分泌激活 ERK 信号转导通路，显著诱导新血管生成，从而提高植入细胞的存活率。
总的来说，这些数据表明，CDH2 过表达不仅增强了培养的 CDH2-hiPSC-CMs 的存活/植入，而且增强了这些细胞的功能整合，从而增强了植入的 CDH2-hiPSC-CMs 在衰竭心脏中的修复特性。
