Development of a Vascularised Cardiac Organoid Platform Reveals a Regulatory Role for Extracellular Matrix Environment on Muscle Functionality

ABSTRACT

Multicellular composition of the heart is important for regulating organ development and responses to injury, however the role of cardiac cell types in organ maturation is not well characterised. In this study we characterised a vascularised cardiac organoid model (vhCO) derived from human pluripotent stem cells to better understand cell-cell interactions in human heart tissue. We show that endothelial cells in vhCO increase organoid force of contraction and enhance the expression of mature sarcomeric proteins and extracellular matrix (ECM) components. Through proteomics, we identified LAMA5 as an important component of the ECM network that enhances force of contraction. Subsequent knockdown of LAMA5 specifically in endothelial cells down regulate force of contraction and reverts the ECM protein profile. We also show that endothelial cells are important for modelling cardiac dysfunction induced by cytokine storm following COVID-19 infection. This study identifies matrix regulatory functions of endothelial cells that govern cardiac maturation and also highlights the importance of organoid multicellularity for disease modelling.