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

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Authors: Heesang Song ; Hye Jin Hwang ; Woochul Chang ; Byeong-Wook Song ; Min-Ji Cha ; Il-Kwon Kim ; Soyeon Lim ; Eun Ju Choi ; Onju Ham ; Chang Youn Lee ; Jun-Hee Park ; Se-Yeon Lee ; Eunmi Choi ; Chungkeun Lee ; Myoungho Lee ; Moon-Hyoung Lee ; Sung-Hou Kim ; Yangsoo Jang ; Ki-Chul Hwang

Citation: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.108(1) : 296-301, 2011

Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

MeSH: Analysis of Variance ; Animals ; Blotting, Western ; Cell- and Tissue-Based Therapy/methods* ; Connexin 43/metabolism ; Cytokines/immunology ; Electrocardiography ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique ; In Situ Nick-End Labeling ; Isoproterenol/pharmacology ; Male ; MesenchymalStemCell Transplantation/methods ; MesenchymalStromalCells/cytology ; MesenchymalStromalCells/metabolism* ; Myocardial Contraction/drug effects ; Myocardial Contraction/physiology* ; Myocardial Infarction/therapy* ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/physiology* ; Norepinephrine/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tetradecanoylphorbol Acetate/metabolism

Keywords: cell therapy ; optical mapping ; differentiation ; heart infarction ; arrhythmia

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.