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(Circulation. 2007;116:917-927.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Preservation of Left Ventricular Function and Attenuation of Remodeling After Transplantation of Human Epicardium-Derived Cells Into the Infarcted Mouse Heart

E.M. Winter, MD; R.W. Grauss, MD; B. Hogers, PhD; J. van Tuyn, MSc; R. van der Geest, PhD; H. Lie-Venema, PhD; R. Vicente Steijn, MSc; S. Maas, BSc; M.C. DeRuiter, PhD; A.A.F. deVries, PhD; P. Steendijk, PhD; P.A. Doevendans, MD, PhD; A. van der Laarse, PhD; R.E. Poelmann, PhD; M.J. Schalij, MD, PhD; D.E. Atsma, MD, PhD; A.C. Gittenberger-de Groot, PhD

From the Departments of Anatomy & Embryology (E.M.W., B.H., H.L.-V., R.V.S., S.M., M.C.D., R.E.P., A.C.G.-d.G.), Cardiology (R.W.G., J.v.T., P.S., A.v.d.L., M.J.S., D.E.A.), Molecular Cell Biology (J.v.T., A.A.F.d.V.), and Radiology (R.v.d.G.), Leiden University Medical Center, Leiden, The Netherlands; and Department of Cardiology, University Medical Center Utrecht (P.A.D.), Utrecht, The Netherlands.

Correspondence to Professor Dr A.C. Gittenberger-de Groot, Leiden University Medical Center, Department of Anatomy and Embryology, Einthovenweg 20, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail acgitten{at}lumc.nl

Received October 4, 2006; accepted June 20, 2007.

Background— Proper development of compact myocardium, coronary vessels, and Purkinje fibers depends on the presence of epicardium-derived cells (EPDCs) in embryonic myocardium. We hypothesized that adult human EPDCs might partly reactivate their embryonic program when transplanted into ischemic myocardium and improve cardiac performance after myocardial infarction.

Methods and Results— EPDCs were isolated from human adult atrial tissue. Myocardial infarction was created in immunodeficient mice, followed by intramyocardial injection of 4x10⁵ enhanced green fluorescent protein–labeled EPDCs (2-week survival, n=22; 6-week survival, n=15) or culture medium (n=24 and n=18, respectively). Left ventricular function was assessed with a 9.4T animal MRI unit. Ejection fraction was similar between groups on day 2 but was significantly higher in the EPDC-injected group at 2 weeks (short term), as well as after long-term survival at 6 weeks. End-systolic and end-diastolic volumes were significantly smaller in the EPDC-injected group than in the medium-injected group at all ages evaluated. At 2 weeks, vascularization was significantly increased in the EPDC-treated group, as was wall thickness, a development that might be explained by augmented DNA-damage repair activity in the infarcted area. Immunohistochemical analysis showed massive engraftment of injected EPDCs at 2 weeks, with expression of -smooth muscle actin, von Willebrand factor, sarcoplasmic reticulum Ca²⁺-ATPase, and voltage-gated sodium channel (-subunit; SCN5a). EPDCs were negative for cardiomyocyte markers. At 6-weeks survival, wall thickness was still increased, but only a few EPDCs could be detected.

Conclusions— After transplantation into ischemic myocardium, adult human EPDCs preserve cardiac function and attenuate ventricular remodeling. Autologous human EPDCs are promising candidates for clinical application in infarcted hearts.

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