Role of nitric oxide/cGMP signaling in cell-meidated cardiac repair.

The presented post-doctoral research project aims to characterize alternative sources of cells for regenerative purposes to target myocardial loss after infarction. Contrary to former axioms, recent studies have shown that adult heart harbors niches of cardiac resident stem or progenitor cells (CSC) with self-renewal capacity. The molecular signals that regulate self-renewal or commitment to differentiation of these CSCs, remain unknow. Because NO stimulates embryonic stem cell differentiation, we propose to test the hypothesis that nitric oxide-cyclic guanosine monophosphate (NO/cGMP) signaling modulates CSC renewal and differentiation. Isolated CSC populations from transgenic mice with cardiac-restricted NO synthase 3 overexpression (NOS3-TG) or soluble guanylate cyclase alpha-1 inactivation will be phenotyped using clonogenicity, proliferation and multipotency assays. Differentiation of CSCs toward cardiomyocytes in vitro, followed by advanced transcriptional profiling and molecular imaging, will be investigated in the presence or absence of NO-donors and neonatal cardiomyocytes from NOS3-TG mice. In translational studies we will isolate endogenous CSCs from peri-operative human cardiac biopsies and study their phenotype in relation to to age and disease severity. Finally, we will test the therapeutic effect of CSCs in a well-established porcine ischemia-reperfusion model using hemodynamic monitoring, multimodal imaging including cell tracking and post-mortem histologic analysis.

Keywords:Cardiomyogenesis, Myocardial protection, Myocardial infarction, Guanylate cyclase, Nitric oxide, Cardiac dtem cell

Disciplines:Cardiac and vascular medicine