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(Circulation. 2005;111:2486-2493.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Stimulation of Paracrine Pathways With Growth Factors Enhances Embryonic Stem Cell Engraftment and Host-Specific Differentiation in the Heart After Ischemic Myocardial Injury

Theo Kofidis, MD^*; Jorg L. de Bruin, MS^*; Toshiyuki Yamane, PhD; Masashi Tanaka, MD; Darren R. Lebl, MS; Rutger-Jan Swijnenburg, MS; Irving L. Weissman, MD; Robert C. Robbins, MD

From the Department of Cardiothoracic Surgery, Falk Research Center (T.K., J.L.d.B., M.T., D.R.L., R.S., R.C.R.), and Department of Pathology (T.Y., I.L.W.), Stanford University Medical School, Stanford, Calif.

Reprint requests to Theo Kofidis, MD, Cardiothoracic Surgery/Falk Research Center, Second Floor, Stanford University Medical School, 300 Pasteur Dr, Stanford, CA 94305. E-mail tkofidis{at}stanford.edu

Received June 9, 2004; revision received January 4, 2005; accepted January 4, 2005.

Background— Growth factors play an essential role in organogenesis. We examine the potential of growth factors to enhance cell engraftment and differentiation and to promote functional improvement after transfer of undifferentiated embryonic stem cells into the injured heart.

Methods and Results— Green fluorescent protein (GFP)–positive embryonic stem cells derived from 129sv mice were injected into the ischemic area after left anterior descending artery ligation in allogenic (BALB/c) mice. Fifty nanograms of recombinant mouse vascular endothelial growth factor, fibroblast growth factor (FGF), and transforming growth factor (TGF) was added to the cell suspension. Separate control groups were formed in which only the growth factors were given. Echocardiography was performed 2 weeks later to evaluate heart function (fractional shortening [FS]), end-diastolic diameter, and left ventricular wall thickness). Hearts were harvested for histology (connexin 43, -sarcomeric actin, CD3, CD11c, major histocompatability complex class I, hematoxylin-eosin). Degree of restoration (GFP-positive graft/infarct area ratio), expression of cardiac markers, host response, and tumorigenicity were evaluated. Cell transfer resulted in improved cardiac function. TGF-ß led to better restorative effect and a stronger expression of connexin 43, -sarcomeric actin, and major histocompatability complex class I. TGF-ß and FGF retained left ventricular diameter. FS was better in the TGF-ß, FGF, and embryonic stem cells-only group compared with left anterior descending artery-ligated controls. Growth factors with cells (TGF-ß, FGF) resulted in higher FS and smaller end-diastolic diameter than growth factors alone.

Conclusions— Growth factors can promote in vivo organ-specific differentiation of early embryonic stem cells and improve myocardial function after cell transfer into an area of ischemic lesion. TGF-ß should be considered as an adjuvant for myocardial restoration with the use of embryonic stem cells.

Key Words: infarction • growth substances • myocytes • cells

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