Abstract 81: End-Stage Human Failing Heart Increases Functional Cardiac Progenitor Cells

Abstract

Background: Human cases of end-stage heart failure provide the rare opportunity to test whether the cells within these hearts exhibit different phenotypic characteristics than those in healthy hearts. We tested whether the failing heart, as it reverses to a well-known fetal reprogramming state, also compensates by increasing the number of functional cardiac progenitor cells. Methods and Results: We examined samples from end-stage human failing hearts and also normal human hearts to quantitate the expression of various cardiac progenitor markers, by immunofluorescence, flow cytometry and RT-PCR. We further tested whether the cardiac progenitor cells were functional in a rodent model of myocardial infarction. All the failing end-stage hearts (N=13) reversed to a fetal state by switching their myosin heavy chain isoforms from beta to alpha. Additionally, atrial natriuretic factor was increased. Compared to normal congenital myocardium, failing end-stage hearts had a 2 to 5 fold increase in the number of C-kit+ and ISL-1+ cardiac progenitor cells (P<0.5). The numbers of cardiac progenitor cells was highest in the right atria as compared to other chambers of the end-stage heart. Cardiac progenitor cells isolated from failing hearts expressed several stemness markers that were upregulated compared to normal human hearts. FACS and IF analysis demonstrated significantly (P<0.5) higher c-kit expression in CDCs derived from end stage patients compare to normal congenital myocardium. Also, there was a tendency for increased FLK1 and Sca-1 expression in CM patients respectively. Transplanted cardiac progenitor cells from end-stage hearts promoted greater myocardial regeneration and functional improvement in the infarcted rat myocardium than transplanted cardiac progenitor cells derived from normal congenital patients (EF=57+3 vs. 41.5±3, P<0.05). Conclusion: Our results show an increase of progenitor cells within the end-stage heart that have the functional potential to regenerate the myocardium. Stimulating the differentiation and increasing the population of cardiac progenitor cells may provide a novel therapeutic strategy for these end-stage hearts.