Functional microvascularization of human myocardium in vitro

Abstract

Summary: In this study, we report static and perfused models of human myocardial-microvascular interaction. In static culture, we observe distinct regulation of electrophysiology of human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) in co-culture with human cardiac microvascular endothelial cells (hCMVECs) and human left ventricular fibroblasts (hLVFBs), including modification of beating rate, action potential, calcium handling, and pro-arrhythmic substrate. Within a heart-on-a-chip model, we subject this three-dimensional (3D) co-culture to microfluidic perfusion and vasculogenic growth factors to induce spontaneous assembly of perfusable myocardial microvasculature. Live imaging of red blood cells within myocardial microvasculature reveals pulsatile flow generated by beating hiPSC-CMs. This study therefore demonstrates a functionally vascularized in vitro model of human myocardium with widespread potential applications in basic and translational research. Motivation: In vivo, capillaries communicate with beating myocardium to regulate heart homeostasis, with disruption of communication between microvascular endothelial cells (MVECs) and cardiomyocytes (CMs) causing transition from healthy to disease phenotype. However, much remains unknown about the molecular mechanisms related to CM-EC communication. This had led to a lack of treatment options for diseases in which the myocardial microvascular is compromised, such as cardiac microvascular dysfunction (CMD). Our understanding has been limited by a lack of in vitro models that recapitulate microvascular architectures and the contractile and hemodynamic biomechanics of the beating heart.

Keywords

• cardiac physiology
• stem cell-derived models
• microvasculature
• electrophysiology
• cardiomyocyte
• endothelial cell