title: Insulin-like growth factor promotes engraftment, differentiation, and functional improvement after transfer of embryonic stem cells for myocardial restoration.
abstract: 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 10(5)) 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.
authors.affiliation: Cardiothoracic Surgery, Falk Research Center, Stanford University Medical School, Stanford, CA 94305, USA. tkofidis@stanford.edu
authors.forename: Theo
authors.initials: T
authors.lastname: Kofidis
authors.forename: Jorg L
authors.initials: JL
authors.lastname: de Bruin
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamane
authors.forename: Leora B
authors.initials: LB
authors.lastname: Balsam
authors.forename: Darren R
authors.initials: DR
authors.lastname: Lebl
authors.forename: Rutger-Jan
authors.initials: RJ
authors.lastname: Swijnenburg
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods*; D002454:Cell Differentiation; D017690:Cell Transplantation / Q000379:methods*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007249:Inflammation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D017202:Myocardial Ischemia / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors
chemical_list: D000199:Actins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D007334:Insulin-Like Growth Factor I