Abstract 5602: The Transcription Factor Islet-1: A Novel Gene Target for Future Cardiac Repair?

Abstract

The LIM-homeobox transcription factor isl1 plays a crucial role during heart embryogenesis. Embryonic isl1+ precursors give rise to over two-thirds of the heart and to its subsequent lineages: cardiac muscle, smooth muscle and endothelium. Interestingly, a subset of Isl1+ progenitors remains embedded in the postnatal heart. In the current study, we investigated whether isl1 is expressed in adult mesenchymal stem cells (MSCs), and after experimental myocardial infarction (MI). Additionally, we examined whether isl1 overexpression in MSCs could promote their vasculogenic properties, and whether intramyocardial gene transfer of naked DNA encoding isl1 could promote a functional recovery after MI. We used the transgenic mice isl1/cre/Z/EG , in order to detect isl1 expression in MSCs of adult mice, complemented by qRT-PCR and immunostaining for isl1 detection in rat- MSCs. Four weeks after MI induction, isl1 expression was assessed in bone marrow and spleen cells by qRT-PCR and immunostaining. Isl1 was retrovirally transduced to MSCs. Endothelial markers were examined by FACS and tube formation capacity was assessed on matrigel. Furthermore, intramyocardial injection of plasmid encoding isl1 to mice after ligation of the LAD was performed. We report for the first time, the identification of isl1+ progenitors in adult bone marrow. The number of isl1+ progenitors increased after in vitro cell culture, and also in the splenocytes after acute experimental myocardial infarction. Isl1 overexpression in MSCs promoted their differentiation towards endothelium. Finally, isl1 gene transfer to the peri-infarct region after MI induction resulted in partial salvage of ventricular function evident by echocardiography. Thus, the isl1 gene may stand as an attractive target for future cell based therapy for regenerative myocardial dysfunction.