Chemical Genetic Approach to Production of hESC-derived Cardiomyocytes
Adult heart muscle cells retain negligible proliferative capacity and this underlies the inability of the heart to replace muscle cells that are lost to injury, such as infarct, and underlies progression to heart failure. To date, no stem cell therapiy has produced significant cardiomyocyte replacement. Instead, transplanted cells, if they persist at all, produce endothelial cells or fibroblasts and the ameliorating effects on heart function that have been reported have been achieved by improving contractility, perfusion or other processes that are impaired in the failing heart. This proposal is to develop specific reagents and ultimately drugs to stimulate regeneration. Our approach integrates advances in stem cell biology, high-throughput (HT) biology, informatics and proteomics to identify small molecules, proteins and signal transduction pathways that control heart muscle formation from human embryonic stem cells (hESCs). High throughput assays will be developed and implemented to identify genes, signaling proteins, and small molecules that that control important steps in the differentiation, proliferation, and maturation of cardiac cells. Computer modeling and informatics will be used to identify and validate the signaling pathways that direct these critical processes. The discovery of small molecules and pathways will lead to protocols for 1) efficient directed differentiation of cardiomyogenic precursors from hESCs for research into transplantation and toxicology, 2) biotech reagents to stimulate cardiomyocyte renewal through directed differentiation of hESCs, and 3) cellular targets or lead compounds to develop drugs that stimulate regeneration from endogenous cells.
Burnham Institute for Medical Research