Cardiomyocytes from phorbol myristate acetate-activated mesenchymal stem cells restore electromechanical function in infarcted rat hearts

Abstract

Despite the safety and feasibility of mesenchymal stem cell (MSC) therapy, an optimal cell type has not yet emerged in terms of electromechanical integration in infarcted myocardium. We found that poor to moderate survival benefits of MSC-implanted rats were caused by incomplete electromechanical integration induced by tissue heterogeneity between myocytes and engrafted MSCs in the infarcted myocardium. Here, we report the development of cardiogenic cells from rat MSCs activated by phorbol myristate acetate, a PKC activator, that exhibited high expressions of cardiac-specific markers and Ca 2+ homeostasis-related proteins and showed adrenergic receptor signaling by norepinephrine. Histological analysis showed high connexin 43 coupling, few inflammatory cells, and low fibrotic markers in myocardium implanted with these phorbol myristate acetate-activated MSCs. Infarct hearts implanted with these cells exhibited restoration of conduction velocity through decreased tissue heterogeneity and improved myocardial contractility. These findings have major implications for the development of better cell types for electromechanical integration of cell-based treatment for infarcted myocardium.cell therapy | optical mapping | differentiation | heart infarction | arrhythmia

Nanothin Coculture Membranes with Tunable Pore Architecture and Thermoresponsive Functionality for Transfer-Printable Stem Cell-Derived Cardiac Sheets

“…3,43À45 The transplantation of MSCs that express cardiac biomarkers was reported to have better reparative effects. 46,47 Thus, cardiac differentiation of MSCs ex vivo prior to transplantation is a high-priority requirement for improved therapeutic efficacy of MSCs for cardiac repair. As coculturing with cardiomyoblasts was shown to promote cardiac-lineage differentiation, 48 we investigated whether the cardiac differentiation of MSCs could be achieved through coculture with H9C2s on NTHP membranes.…”

MicroRNAs as novel regulators of stem cell fate

“…The fate of HSCs is regulated by small molecules that promote self-renewal [181][182][183] . Using small molecules, multipotent MSCs can differentiate into various non-hematopoietic cells, such as chondrocytes [134,184] , osteoblasts [185,186] , hepatocytes [187] , cardiomyocytes [188,189] , adipocytes [190,191] and neuronal-like cells [192][193][194] . Additionally, the maintenance of MSCs is associated with the Wnt signaling pathway [195,196] .…”

Improved conduction and increased cell retention in healed MI using mesenchymal stem cells suspended in alginate hydrogel

“…Current therapies for SCD are largely inadequate, making it a major unresolved clinical problem. Cell therapy has emerged as a promising approach for the treatment of MI [1, 2] and has been associated with restoration of electrical activity and reduced arrhythmia vulnerability [3–5]. For example, mesenchymal stem cells (MSCs) are the subject of ongoing clinical trials [6], and results to date demonstrate that MSCs are safe and improve function [7–9].…”