Antiarrhythmic versus arrhythmogenic potentials of mesenchymal stem cells, paracrine factors, and cardiogenic cells

Abstract

The purpose of this study was to evaluate the anti-arrhythmic potential of mesenchymal stem cells (MSCs), paracrine media (PM) secreted from MSCs and cardiogenic cells differentiated from MSCs. To investigate the effect of MSCs, paracrine factors secreted from MSCs, and cardiogenic cells differentiated from MSCs on arrhythmogenicity in rats with MI, we injected PM secreted under hypoxic-, normoxic conditions (hypoxic PM and normoxic PM), MSCs, and cardiogenic cells into the border zone of infarcted myocardium in rats. We found that the injection of hypoxic PM, but not normoxic PM, markedly restored conduction velocities, suppressed focal activity, and prevented sudden arrhythmic deaths in rats. Underlying this electrophysiological alteration was a decrease in fibrosis, restoration of connexin 43, alleviation of Ca2+ overload, and recovery of Ca2+-regulatory ion channels and proteins, all of which is supported by proteomic data showing that several paracrine factors including bFGF, IGF-1, HGF, and EF-hand-domain-containing 2 are potential mediators. MSCs injection did not reduce or prevent arrhythmogenicity, suggesting that anti-arrhythmic or pro-arrhythmic potential of MSCs is mainly dependent on paracrine factors. In contrast, cardiogenic cells injection reduced arrhythmogenicity by improving conduction velocity and acquiring homogeneity of conduction vector. Paracrine molecules of MSCs depending on surrounding environment, hypoxic or normoxic status, determines anti-arrhythmic potential of MSCs. MSCs did not affect arrhythmogenicity but cardiogenic cells differentiated from MSCs had anti-arrhythmic effect by attenuating tissue inhomogeneity.