Published Online
on May 9, 2005

A more recent version of this article appeared on May 17, 2005

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Submitted on June 9, 2004
Revised on January 4, 2005
Accepted on January 4, 2005

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, and 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.

^* To whom correspondence should be addressed. E-mail: tkofidis{at}stanford.edu.

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- led to better restorative effect and a stronger expression of connexin 43, -sarcomeric actin, and major histocompatability complex class I. TGF- and FGF retained left ventricular diameter. FS was better in the TGF-, FGF, and embryonic stem cells-only group compared with left anterior descending artery-ligated controls. Growth factors with cells (TGF-, 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- 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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