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Stem Cells 2004;22:1239-1245 www.StemCells.com
© 2004 AlphaMed Press

Insulin-Like Growth Factor Promotes Engraftment, Differentiation, and Functional Improvement after Transfer of Embryonic Stem Cells for Myocardial Restoration

Theo Kofidisa, Jorg L. de Bruina, Toshiyuki Yamaneb, Leora B. Balsama, Darren R. Lebla, Rutger-Jan Swijnenburga, Masashi Tanakaa, Irving L. Weissmanb, Robert C. Robbinsa

a Cardiothoracic Surgery, Falk Research Center, and
b Department of Pathology, Stanford University Medical School, Stanford, California, USA

Key Words. Growth substances • Myocardial infarction • Cell transfer • Embryonic stem cells

Correspondence: Theo Kofidis, M.D., Cardiothoracic Surgery, Falk Research Center, 2nd Floor, Stanford University Medical School, 300 Pasteur Dr., Stanford, CA 94305. Telephone: 650-723-5408; Fax: 650-725-846; e-mail: tkofidis{at}stanford.edu

Insulin-like growth factor-1 (IGF-1) promotes myocyte proliferation and can reverse cardiac abnormalities when it is administered in the early fetal stage. Supplementation of a mouse embryonic stem cell (ESC) suspension with IGF-1 might enhance cellular engraftment and host organ-specific differentiation after injection in the area of acute myocardial injury. In the study reported here, we sought to enhance the restorative effect of ESCs in the injured heart by adding IGF-1 to the injected cell population. Green fluorescent protein (GFP)–labeled sv129 ESCs (2.5 x 105) were injected into the ischemic area after left anterior descending (LAD) artery ligation in BalbC mice. Recombinant mouse IGF-1 (25 ng) was added to the cell suspension prior to the injection (n = 5). Echocardiography was performed before organ harvest 2 weeks later. The degree of restoration (ratio of GFP+ to infarct area), expression of cardiac markers by GFP+ cells, inflammatory response, and tumorigenicity were evaluated. Mice with LAD ligation only (n = 5) and ESC transfer without IGF-1 (n = 5) served as controls. ESCs formed viable grafts and improved cardiac function. Left ventricular wall thickness was higher in the IGF-1 group (p = .025). There was a trend toward higher fractional shortening in the IGF-treated group. Histological analysis demonstrated that IGF-1 promoted expression of {alpha}-sarcomeric actin ( p = .015) and major histocompatibility complex class I ( p = .01). IGF did not affect the cellular response to the donor cells or tumorigenicity. IGF-1 promotes expression of cardiomyocyte phenotype in ESCs in vivo. It should be considered as an adjuvant to cell transfer for myocardial restoration.




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