Paracrine factor-mediated stem cell differentiation to cardiac myocytes
Cardiovascular disease is the leading cause of morbidity and mortality in the United States with >50% of mortality attributable to coronary artery disease that leads to a heart attack. A heart attack results from death of heart tissue and leads to loss of heart function. Because the heart is composed of muscle cells that are not able to regenerate, two options exist to protect people from reduced heart function after a heart attack begins: 1) prevent the extent of injury or 2) regenerate the dead tissue and create a more functional heart muscle. The first option is the current approach used but it has only limited effectiveness, in part because it is difficult to predict when someone is going to have a heart attack. The second option, the main goal of this project, is more challenging but offers potential for a wide variety of individuals with injured hearts.
Studies with experimental animals have had limited success in terms of generating functional heart tissue using various types of stem cell types. Heart cells exist as a cohesive network that meets the energy demands of the body by pumping blood in a rhythmic manner. The futility of previous studies has been to introduce stem cells into this network in the hope that the cells will be able to graft onto the damaged tissue and create functional networks with existing cells to generate a better functioning heart. Unfortunately, this has not occurred. The cells that are introduced into the damaged heart are eliminated without becoming permanent members of the “cardiac network”.
In this study, we propose a new approach that exploits a critical feature of the structure of the heart: cardiac muscle cells are surrounded by another cell type, cardiac fibroblasts, which produce a number of as-yet inadequately defined factors that likely contribute to the health and function of the muscle cells. The goal of our proposed studies is to understand how cardiac fibroblasts are able to maintain and, in the case of human embryonic stem cells (hESC), to create an environment that favors differentiation of cells to be ones able to contract and improve overall cardiac function, in particular perhaps to regenerate dead heart tissue. Fibroblasts are a vital part of the network of cardiac cells. We thus will first determine if hESCs grown together with cardiac fibroblasts are able to coax the stem cells to turn into heart cells. Fibroblasts are known to make and release factors that then act on nearby cells but the full complement of these factors is not known. Our second aim is to determine which factors are released by fibroblasts that are capable of transforming hESC to heart cells. In the final aim, we will test if hESC cells grown with cardiac fibroblasts or factors made by fibroblasts will create an environment, when tested in mice, for long term health and benefit in terms of heart function.
Cardiovascular disease is the leading cause of morbidity and mortality in the United States as well as in California with >50% of mortality attributable to coronary artery disease primarily leading to a heart attack. The current proposal aims to determine if human embryonic stem cells can be coaxed to become heart cells by interaction with cardiac fibroblasts, which in a functioning heart are essential neighbors of heart muscle cells. The information gained from these studies will help in the development of therapies that will restore cardiac function following injury, in particular heart attacks, that destroys cells in the heart that are necessary for normal function. Thus, Californians would potentially benefit from improved health by virtue of success in the proposed studies. Given the widespread occurrence of coronary artery disease and heart failure, success in the proposed studies that would identify key factors produced by cardiac fibroblasts that facilitate health and function of cardiac myocytes would likely lead to the development of novel drugs that exploit such findings and that would thus potentially contribute to the benefit of the California economy.