Heesang Songa,1, Hye Jin Hwangb,1, Woochul Changb,1,2, Byeong-Wook Songb,c, Min-Ji Chab,c, Il-Kwon Kimb,c, Soyeon Limb,3, Eun Ju Choib,c, Onju Hamb,c, Chang Youn Leed, Jun-Hee Parkd, Se-Yeon Leeb,c, Eunmi Choib,e, Chungkeun Leef, Myoungho Leef, Moon-Hyoung Leeg, Sung-Hou Kimd,h,4, Yangsoo Jangb,c,e,g,4, and Ki-Chul Hwangb,c,e,4
aResearch Institute of Science for Aging, Yonsei University, Seoul 120-752, Korea;
bCardiovascular Research Institute and
cBrain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea;
dDepartment of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul 120-749, Korea;
eSeverance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea;
fDepartment of Electrical and Electronic Engineering, Yonsei University, Seoul 120-749, Korea;
gCardiology Division, Yonsei University College of Medicine, Seoul 120-752, Korea; and
hDepartment of Chemistry, University of California, Berkeley, CA 94702
2Present address: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
3Present address: Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642.
Contributed by Sung-Hou Kim, October 26, 2010 (sent for review September 2, 2010)
1H.S., H.J.H., and W.C. contributed equally to this work.
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 Ca2+ 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
4To whom correspondence may be addressed.
Author contributions: S.-H.K., Y.J., and K.-C.H. designed research; H.S., H.J.H., W.C., B.-W.S., M.-J.C., I.-K.K., S.L., E.J.C., O.H., C.Y.L., J.-H.P., S.-Y.L., E.C., C.L., M.L., and M.-H.L. performed research; S.-H.K., Y.J., and K.-C.H. contributed new reagents/analytic tools; H.S., H.J.H., W.C., B.-W.S., M.-J.C., I.-K.K., S.L., E.J.C., O.H., C.Y.L., J.-H.P., S.-Y.L., E.C., C.L., M.L., M.-H.L., S.-H.K., Y.J., and K.-C.H. analyzed data; and S.-H.K., Y.J., and K.-C.H. wrote the paper.
The authors declare no conflict of interest.
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