Atsushi Tachibana1, Michelle R Santoso1, Morteza Mahmoudi1, Praveen Shukla1, Lei Wang1, Mihoko Bennett1, Andrew B Goldstone1, Mouer Wang1, Masahiro Fukushi1, Antje D Ebert1, Y Joseph Woo1, Eric Rulifson1, Phillip C Yang2. 1. From the Division of Cardiovascular Medicine (A.T., M.R.S., M.M., P.S., L.W., M.W., A.D.E., E.R., P.C.Y.), Division of Neonatal and Developmental Medicine (M.B.), and Department of Cardiothoracic Surgery (A.B.G., Y.J.W.), Stanford University, CA; Department of Radiological Sciences, Tokyo Metropolitan University, Japan (A.T., M.F.); Department of Critical Care Medicine, 2nd Affiliated Hospital of Guangzhou University of Chinese Medicine, China (L.W.); Department of Cardiology and Pneumonology, Göttingen University Medical Center, Germany (A.D.E.); and German Center for Cardiovascular Research, Partner Site Göttingen, Germany (A.D.E.). 2. From the Division of Cardiovascular Medicine (A.T., M.R.S., M.M., P.S., L.W., M.W., A.D.E., E.R., P.C.Y.), Division of Neonatal and Developmental Medicine (M.B.), and Department of Cardiothoracic Surgery (A.B.G., Y.J.W.), Stanford University, CA; Department of Radiological Sciences, Tokyo Metropolitan University, Japan (A.T., M.F.); Department of Critical Care Medicine, 2nd Affiliated Hospital of Guangzhou University of Chinese Medicine, China (L.W.); Department of Cardiology and Pneumonology, Göttingen University Medical Center, Germany (A.D.E.); and German Center for Cardiovascular Research, Partner Site Göttingen, Germany (A.D.E.). phillip@stanford.edu.
Abstract
RATIONALE: Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear. OBJECTIVE: To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model. METHODS AND RESULTS: Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups. CONCLUSIONS: This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.
RATIONALE: Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear. OBJECTIVE: To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murinemyocardial injury model. METHODS AND RESULTS: Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups. CONCLUSIONS: This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.
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