Heart regeneration with engineered myocardial tissue

Abstract

Heart disease is the leading cause of morbidity and mortality worldwide, and regenerative therapies that replace damaged myocardium could benefit millions of patients annually. The many cell types in the heart, including cardiomyocytes, endothelial cells, vascular smooth muscle cells, pericytes, and cardiac fibroblasts, communicate via intercellular signaling and modulate each other's function. Although much progress has been made in generating cells of the cardiovascular lineage from human pluripotent stem cells, a major challenge now is creating the tissue architecture to integrate a microvascular circulation and afferent arterioles into such an engineered tissue. Recent advances in cardiac and vascular tissue engineering will move us closer to the goal of generating functionally mature tissue. Using the biology of the myocardium as the foundation for designing engineered tissue and addressing the challenges to implantation and integration, we can bridge the gap from bench to bedside for a clinically tractable engineered cardiac tissue.

Keywords: cardiac tissue engineering; cardiovascular regenerative medicine; coronary artery disease; heart failure; microvessel engineering; myocardial infarction; stem cells.

Figure 1

Architecture of myocardial cells in a healthy rat heart. (a–c) Alpha-actinin-positive cardiomyocytes (red) show striations in the longitudinal plane (b) and clearly make up the bulk of the tissue as viewed in cross section (c). Vimentin-positive cells (fibroblasts and ECs; green) are tucked between the cardiomyocytes. (d–f) In a serial section to panel a, ECs (RECA, red) show capillaries aligning with the main axis of the cardiomyocytes (e) and 3–4 capillaries surrounding each cardiomyocyte as viewed in cross section (f). Larger vessels have SMA-positive (green) SMCs surrounding the ECs (d). Abbreviations: ECs, endothelial cells; RECA, rat endothelial cell antigen; SMA, smooth muscle alpha-actin; SMCs, smooth muscle cells.

Figure 2

Schematic diagram depicting vascularization strategies for tissue-engineered myocardium. (a) Approaches to make a scaffold proangiogenic include tailoring scaffold porosity, microfluidic channel size and distribution, angiogenic growth factor release, cell coculture conditions, and combinations thereof. (b) In vivo prevascularization of scaffolds can be achieved extrinsically by implanting them into vascularized areas (such as in the subcutaneous space or onto the omentum or peritoneum) or intrinsically by implanting them using an artificially created arteriovenous loop in a protected chamber. (c) In vitro prevascularization is achieved by coculturing vascular cells within the (templated) scaffold in the presence of angiogenic factors. (d) Vascularized constructs are implanted onto infarcted myocardium and anastomose with the host microvasculature in order to restore lost tissue and cardiac function.