N-cadherin overexpression enhances the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes in infarcted mouse hearts

Abstract

Aims 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. Methods and results 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. Conclusion 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.

MAPK/ERK Pathway as a Central Regulator in Vertebrate Organ Regeneration

“…Moreover, proper coronary vasculature morphogenesis and neovasculature stabilization require tight control of cell-cell adhesion among homotypic and heterotypic cells, for instance, endothelial cells and CMs. In the MI rat model, over-expression of N-cadherin significantly increases ERK activity, which in turn promotes vascular endothelial growth factor (VEGF) expression [50]. The up-regulated VEGF functions in a paracrine manner contributing to neovascularization and integration of regenerated CMs.…”

Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart

“…However, Lou et al . 54 showed that cell engraftment could be improved by overexpressing N-cadherin, a protein that mediates the adhesion between cardiac myocytes (CMs). This also improved their functional integration via paracrine activation of the extracellular signal-regulated kinase (ERK) signal transduction pathway, inducing neo-vasculogenesis and increasing survival of the implanted cells.…”

“…Importantly, in mice that received these cells following MI, infarct size was also reduced and left ventricular (LV) ejection fraction was improved. 54 …”

Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes, in Contrast to Adipose Tissue-Derived Stromal Cells, Efficiently Improve Heart Function in Murine Model of Myocardial Infarction

“…Previous studies have also demonstrated that genetic or electromechanical conditioning of human embryonic stem cell (hESC)-or hiPSC-derived cardiomyocytes enhances their therapeutic potential in animal MI models. For instance, genetically modified hiPSC-CMs expressing N-cadherin enhanced LVEF and decreased infarct size more profoundly than nonmodified cells [24].…”