Intramyokardiale Transplantation von humanen, mit IGF-II transduzierten, endothelialen Progenitorzellen in Nacktratten im akuten Myokardinfarktmodell

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.