Dr. Charles E. Murry

Overview
Myocardial infarctions (heart attacks) are the number one cause of death in the industrialized world. Infarcts occur when a coronary artery becomes obstructed, resulting in the rapid death of myocardium from ischemia (deficiency of blood flow). The heart has no significant intrinsic regenerative ability. As a result, infarcts heal by scar formation, and many patients suffer from heart failure after an infarct. Our group is interested in the biology of myocardial infarction, both in defining the molecular mechanisms that underlie the heart's normal wound healing processes and in developing molecular and cell-based approaches to improve infarct repair. We are a multidisciplinary group, doing basic work in molecular biology and regulation of gene expression, cell biology, tissue engineering, mouse models of disease, and analyses of human tissues. The following serves to highlight some of the work underway in the lab.

Stem Cell Studies
Our lab is working with both adult and embryonic stem cells, with an aim to develop cellular approaches to regenerate the heart. Embryonic stem cell studies have 2 foci at present: derivation of cardiac progenitor cells and early cardiomyocytes using promoter-based selection strategies; and control of stem cell proliferation using a genetic switch (described below).

Our work in adult stem cells began with the discovery in transplanted human hearts that cells from outside the heart could give rise to virtually all components of myocardial tissue, including endothelial cells, smooth muscle cells, perineural Schwann cells and cardiomyocytes. In addition to continuing analysis of human tissues, are goals are to develop mouse models that allow us to identify the progenitor cells, factors that trigger mobilization and homing, and identify the pathways that regulate transdifferentiation of the progenitors to other cell types, particularly cardiomyocytes.

''Molecular Pharmacology'' for Control of Cell Proliferation
We have developed a system that induces cell replication in response to a small, synthetic molecule both in vitro and in vivo. This system may allow us to control proliferation after cell grafting, such that optimal repair of myocardial infarcts can be effected pharmacologically. The system consists of the cytoplasmic domain of the FGF receptor-1, fused to a drug-binding domain. When cells are stably transfected with this construct, administration of a small, bivalent drug will result in FGF receptor dimerization and activation of the FGF receptor's normal signaling pathway. This system works well in skeletal muscle cells and endothelial cells, and we are extending it to control proliferation of stem cell-derived cardiomyocytes.

Tissue Engineering
Tissue engineering is a new discipline that combines the worlds of cell biology, materials science and quantitative approaches to mathematical modeling and analyses typical of engineering. Our goal is to create a ''patch'' of contractile tissue ex vivo and implant this onto an infarcted heart for cardiac repair. Current approaches involve seeding cells onto synthetic, biodegradable scaffolds and utilizing a ''cells in gels'' approach, where cells are seeded into hydrophilic gels containing microencapsulated growth factors and cytokines for timed release.

Regulation of the Heart's Intrinsic Repair Response
A mouse model of myocardial infarction has been developed to take advantage of numerous genetic models. We have defined the time course of endothelial and fibroblast proliferation, as well as the global changes in cardiac geometry that occur after myocardial infarction. We currently are screening knockout strains to define the major mitogens that regulate endothelial cell and fibroblast proliferation post-infarction. Using this approach, bFGF has been identified as a major mitogen for cardiac fibroblasts in the injured heart.