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Sitz, Wibke (2007): Intramyokardiale Transplantation von humanen, mit IGF-II transduzierten, endothelialen Progenitorzellen in Nacktratten im akuten Myokardinfarktmodell. Dissertation, LMU München: Faculty of Veterinary Medicine
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Abstract

Insulin-like growth factors (IGF) are not only mediators of metabolic actions, but also regulate cell growth, differentiation and apoptosis. IGF-II is of particular interest because of its mitogenic effects. It is known that endothelial progenitor cells (EPC) improve myocardial function after acute myocardial infarction. The aim of this study was to investigate whether overexpression of IGF-II in EPC further contributes to improvement in left ventricular function after myocardial infarction. Human CD34+ cells from cord blood were isolated and cultured in adequate cell medium. Early passage EPC were transduced ex vivo by a retroviral vector expression of IGF-II (EPC-IGF-II) or empty vector (EPC-pLXSN) and expanded up to 46 population doublings. Expression levels were confirmed by RT-PCR. Athymic, nude rats were thoracotomized and ligation of the LAD (left anterior descending artery) was performed for 30 minutes before reperfusion was initiated. Vector only transduced EPC or EPC-IGF-II cells were injected immediately after reperfusion in the border of the infarct zone. Serial echocardiographic measurements were performed to analyze left ventricular ejection fraction (EF) up to 2 weeks after myocardial infarction when animals were mercy killed. Transplantation of EPC-derived cells improved left ventricular function after experimental myocardial infarction from 47,3 ± 1,8 % (EF of the control group, n = 11) to 51,4 ± 0,7 % EF 2 weeks after infarction (p < 0,05, n = 9). Overexpression of IGF-II further improved left ventricular ejection fraction to 53,6 ± 0,5 % EF at 2 weeks as compared to empty vector transduced cells (p < 0,05, n = 10). In vitro experiments revealed that IGF-II dose-dependently enhanced the proliferation capacity of H9C2 rat cardiomyoblasts measured by a BrdU incorporation assay. Immunhistological analysis of proliferating cells in the myocardium showed an increased number of Ki67+ cells within the infarct zone 7 days after transplantation of IGF-II overexpressing cells as compared to empty vector transduced cells. It was shown that transplantation of IGF-II overexpressing EPC impaired the infarction size by nearly 20 % in comparison to EPC-pLXSN (p < 0,05). Thus, transplantation of IGF-II overexpressing EPC in acute myocardial infarction may improve myocardial function by enhancing the proliferation capacity of resident cardiomyocyteprogenitors.