Abstract 16573: End-Stage Human Failing Hearts Increase Cardiac Progenitor Cells by Switching to a Developmental Program
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. The number of cardiac progenitor cells was highest in the right atria compared to other chambers of the end-stage heart. Cardiac progenitor cells isolated from failing hearts expressed several stemness markers that were unregulated compared to cardiac progenitor cells from adult heart. Stemness levels were similar to cardiac progenitor cells isolated from neonatal hearts. 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 adult hearts.
Conclusion: Our results show a high level of progenitor cells within the end-stage heart that have the potential to regenerate the myocardium. These end-stage hearts not only reverse back to a fetal state but perhaps more importantly to a developmental state that is not seen in the post-natal heart. Stimulating the differentiation and increasing the population of cardiac progenitor cells may provide a novel therapeutic strategy for these end-stage hearts.
- © 2011 by American Heart Association, Inc.