Abstract 20232: Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration

Background: Heart failure is often caused by loss of cardiac cells that are unable to re-enter the cell cycle for regeneration. Numerous attempts to identify such cell cycle regulators that could induce cell division of cardiomyocytes, or other cell types, have resulted in nuclear division (karyokinesis), but inefficient cleavage into two distinct daughter cells (cytokinesis) and subsequent survival. Such strategies stimulate cell cycle markers in no more than 1% of cardiomyocytes, limiting their utility. Methods and results: Here, we took a combinatorial approach to screen for cell cycle factors and conditions that could recapitulate the fetal state of cardiomyocyte division. We found that ectopic introduction of the Cdk1/CyclinB1 and the Cdk4/CyclinD1 complexes promoted cell division in at least 15% of mouse and human cardiomyocytes in vitro. Rigorous assessment of cell division in vivo with the cardiac specific (α-MHC) Cre-recombinase dependent Mosaic Analysis with Double Markers (MADM) lineage tracing...