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J Thorac Cardiovasc Surg 2006;131:889-897
© 2006 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Homing of intravenously infused embryonic stem cell-derived cells to injured hearts after myocardial infarction

Jiang-Yong Min, MD a , d , Xuling Huang, MD a , Meixiang Xiang, MD, PhD a , b , Achim Meissner, MD c , Yu Chen, MD a , Qingen Ke, MD a , Emel Kaplan, BS a , Jamal S. Rana, MD a , Peter Oettgen, MD, PhD a , James P. Morgan, MD, PhD a , d , *

a Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass
b Second Affiliated Hospital, Medical College of Zhejiang University, Zhejiang, China
c Department of Cardiology, University of Kiel, Kiel, Germany
d Division of Cardiovascular Medicine, Department of Medicine, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass

Received for publication July 20, 2005; revisions received November 23, 2005; accepted for publication December 1, 2005.

* Address for reprints: James P. Morgan, MD, PhD, Division of Cardiovascular Medicine, Department of Medicine, Caritas St. Elizabeth's Medical Center, Cardiovascular Center, Caritas Christi Healthcare System, 736 Cambridge St, Boston, MA 02135 (Email: james.morgan{at}caritaschristi.org).

OBJECTIVE: The present study was designed to test whether intravenously infused embryonic stem cell-derived cells could translocate to injured myocardium after myocardial infarction and improve cardiac function.

METHODS: Cultured embryonic stem cell-derived cells were transfected with green fluorescent protein. Embryonic stem cell-derived cells were administered through the tail vein (approximately 107 cells in 1 mL of medium for each rat) every other day for 6 days in 45 rats after myocardial infarction. Six weeks after myocardial infarction and cell infusion, cardiac function, blood flow, and the numeric density of arterioles were measured to test the benefits of cell therapy. An in vitro Transwell assay was performed to evaluate the embryonic stem cell migration.

RESULTS: Ventricular function, regional blood flow, and arteriole density were significantly increased in rats receiving intravenously infused embryonic stem cell-derived cells compared with control rats after myocardial infarction. Histologic analysis demonstrated that infused embryonic stem cell-derived cells formed green fluorescent protein-positive grafts in infarcted myocardium. Additionally, positive immunostaining for cardiac troponin I was found in hearts after myocardial infarction receiving embryonic stem cell-derived cell infusion that corresponded to the green fluorescent protein-positive staining. The Transwell migration assay indicated that cultured neonatal rat cardiomyocytes with overexpression of tumor necrosis factor {alpha} induced greater migration of embryonic stem cells compared with cardiomyocytes without tumor necrosis factor {alpha} expression.

CONCLUSIONS: Our data demonstrate that intravenously infused embryonic stem cell-derived cells homed to the infarcted heart, improved cardiac function, and enhanced regional blood flow at 6 weeks after myocardial infarction. The in vitro migration assay suggested that such a homing mechanism could be associated with locally released cytokines, such as tumor necrosis factor {alpha}, that are upregulated in the setting of acute myocardial infarction and heart failure.

Abbreviations and Acronyms cTnI = cardiac troponin I; DAPI = 4'-6-diamidino-2-phenylindole; +dP/dtmax = maximum rate of LV systolic pressure increase; –dP/dtmax = maximum rate of LV systolic pressure decrease; EDC = embryonic stem cell-derived cell; ESC = embryonic stem cell; GFP = green fluorescent protein; LV = left ventricular; LVSP = left ventricular systolic pressure; MI = myocardial infarction; TNF = tumor necrosis factor




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