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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 1; pp. 296 - 301
• Main Authors: Song, Heesang, Hwang, Hye Jin, Chang, Woochul, Song, Byeong-Wook, Cha, Min-Ji, Kim, Il-Kwon, Lim, Soyeon, Choi, Eun Ju, Ham, Onju, Lee, Chang Youn, Park, Jun-Hee, Lee, Se-Yeon, Choi, Eunmi, Lee, Chungkeun, Lee, Myoungho, Lee, Moon-Hyoung, Kim, Sung-Hou, Jang, Yangsoo, Hwang, Ki-Chul
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04.01.2011; National Acad Sciences
• Subjects: 12-O-Tetradecanoylphorbol-13-acetate; Acetic acid; Adrenergic receptors; Analysis of Variance; Animals; Biological Sciences; Blotting, Western; Calcium; cardiomyocytes; Cell- and Tissue-Based Therapy - methods; Conduction; Connexin 43; Connexin 43 - metabolism; Contractility; Cytokines - immunology; Dysrhythmias; Electrocardiography; Enzyme-Linked Immunosorbent Assay; Fibrosis; Fluorescent Antibody Technique; Heart; Heart attacks; In Situ Nick-End Labeling; Inflammation; Integration; Isoproterenol - pharmacology; Magnification; Male; Medical treatment; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Mesenchyme; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Myocardial Infarction - therapy; Myocardium; Myocytes; Myocytes, Cardiac - cytology; Myocytes, Cardiac - physiology; Norepinephrine; Norepinephrine - metabolism; Protein kinase C; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic - metabolism; Recovery of function; Research universities; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Stem cells; Sudden death; Tetradecanoylphorbol Acetate - metabolism; Tissues; Transplantation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1015873107

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.