Overcoming Bottlenecks to Cardiac Regenerative Therapy
Heart failure secondary to ischemic disease is a leading cause of morbidity and mortality in California and the developed world. As current therapies do little to rescue cardiac function, there is great interest in the promise of stem cell-based transplantation therapies to repair infarcted myocardium and reverse deterioration of cardiac function. However, there remain several bottlenecks to successful clinical application of stem cell transplantation in patients post myocardial infarction. Some bottlenecks which must be overcome are (1) to obtain a plentiful source of differentiated human ventricular cardiomyocytes (VCs); (2) to develop a method to deliver differentiated VCs to infarcted heart which allows cells to survive and integrate; and (3) to develop non-invasive quantitative imaging techniques to observe transplanted cells and their effects on heart function. To overcome these bottlenecks, we have assembled an interdisciplinary team of cardiovascular physician-scientists with expertise in animal models of cardiovascular disease, physiology, and cardiac inflammation; basic scientists studying cardiovascular disease, development, and stem cells; and bioengineers with expertise in tissue engineering, cardiac mechanics, and biomaterials for delivery of cells to infarcted myocardium.
We have three experimental aims. Aim 1 will utilize new approaches for the differentiation and purification of human embryonic stem cell (hESC)-derived VCs. Success of these new methods will result in a high yield of purified VCs from hESCs which do not contain detectable pluripotent stem cells which might be tumorigenic. Aim 2 addresses the differentiation and yield of VCs transplanted into post-infarct heart by developing novel extracellular matrices that recapitulate the composition and physical properties of normal ventricular myocardium. Successful use of these optimized matrices to deliver hESC-derived VCs to post-infarct myocardium will result in restoration of 30% or more of of the infarct scar to functional ventricular muscle in a mouse myocardial infarction model. Aim 3 addresses the need for non-invasive methods to monitor the fate of transplanted cells and their physiological effects post infarct, and to address potential adverse teratogenic responses after transplantation. Successful completion of this aim will result in validation of new methods suitable for application in pre-clinical and clinical studies that can identify non-invasively cells with potential to develop tumors, the fate of differentiated transplanted VCs, and demonstrate sustained improvement in global and regional ventricular function following cell transplantation in post-infarct mice.
Atherosclerotic coronary artery disease continues to be the major cause of death in California and in the United States as a whole. The reduction, or complete cessation, of blood perfusion associated with subtotal or total coronary artery obstruction gives rise to myocardial dysfunction, potentially lethal arrhythmias, and ultimately cardiomyocyte death and regional infarction. Although a variety of medical, pharmacological and surgical interventions have been developed that attempt to inhibit adverse cardiac remodeling and ensuing heart failure, there remains a pressing need for a new strategy to repair damaged myocardium. Either partial repair, or outright regeneration, of myocardial cellular constituents, most importantly the cardiomyocytes, by cell transplantation provides for the promise of this repair. Our experiments will lead to a new plentiful source of appropriately differentiated human cardiomyocytes for use in cell transplant, a new delivery vehicle that promotes a high yield of surviving differentiated cardiomyocytes in infarcted muscle; and new non-invasive techniques for defining the fate of implanted cells and their impact on ventricular remodeling and function.