Engineering Vascularized Cardiac Muscle Using a Modular Approach
Ischemic heart disease is the most common cause of end-stage heart failure in adults, and a common pathophysiological component of numerous cardiomyopathies and complex congenital heart defects in children. Any strategy to regenerate the heart therefore not only requires replacement of the cardiac myocytes (CMs) killed by the ischemia, but also resolution of the ischemia itself. We have adopted reprogramming strategies to transdifferentiate resident fibroblasts into cardiomyocyte-like cells, and to build functional microvasculature essential to sustain their metabolic demands. Both of these processes are regulated by cues from the cellular microenvironment; however, environments supportive of reprogramming may not be ideal for vasculariztion, and vice-a-versa. This project will utilize modular biomaterial strategies to generate two discrete microenvironments. The first will support cardiac reprogramming with high efficiencies, and the second will support the formation of vascularized microtissues. We will then integrate these discrete environments into a larger engineered heart tissue construct in which the vascular modules inosculate with one another to form interconnected vascular beds capable of supporting the function of the cardiac muscle modules.