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.

• Authors: Xi Lou, Meng Zhao, Chengming Fan, Vladimir G Fast, Mani T Valarmathi, Wuqiang Zhu, Jianyi Zhang
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 116 Issue 3 Pg. 671-685 (03 01 2020) ISSN: 1755-3245 [Electronic] England
• PMID: 31350544 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected].

Chemical References

• Antigens, CD
• CDH2 protein, human
• Cadherins
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Action Potentials
• Animals
• Antigens, CD (genetics, metabolism)
• Apoptosis
• Cadherins (genetics, metabolism)
• Cell Differentiation
• Cell Line
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Induced Pluripotent Stem Cells (metabolism, transplantation)
• Mice, Inbred NOD
• Mice, SCID
• Myocardial Infarction (metabolism, pathology, physiopathology, surgery)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (metabolism, pathology, transplantation)
• Neovascularization, Physiologic
• Paracrine Communication
• Proto-Oncogene Proteins c-akt (metabolism)
• Recovery of Function
• Regeneration
• Signal Transduction
• Stroke Volume
• Up-Regulation
• Ventricular Function, Left