Vascular cells improve functionality of human cardiac organoids

Crosstalk between cardiac cells is critical for heart performance. Here we show that vascular cells within hu-man cardiac organoids (hCOs) enhance their maturation, force of contraction, and utility in disease modeling. Herein we optimize our protocol to generate vascular populations in addition to epicardial, fibroblast, and cardiomyocyte cells that self-organize into in-vivo-like structures in hCOs. We identify mechanisms of communication between endothelial cells, pericytes, fibroblasts, and cardiomyocytes that ultimately contribute to cardiac organoid maturation. In particular, (1) endothelial-derived LAMA5 regulates expression of mature sarcomeric proteins and contractility, and (2) paracrine platelet-derived growth factor receptor (3 (PDGFR(3) signaling from vascular cells upregulates matrix deposition to augment hCO contractile force. Finally, we demonstrate that vascular cells determine the magnitude of diastolic dysfunction caused by in-flammatory factors and identify a paracrine role of endothelin driving dysfunction. Together this study high-lights the importance and role of vascular cells in organoid models.

Automated summary

Communication between different types of cardiac cells is crucial for optimal heart performance. Our study demonstrates that vascular cells in human cardiac organoids improve their maturation, contraction strength, and disease modeling capabilities. We have developed a protocol to generate vascular populations along with other cell types, and these cells self-organize into structures resembling in-vivo conditions. We have identified specific mechanisms of communication between endothelial cells, pericytes, fibroblasts, and cardiomyocytes, which contribute to the maturation of cardiac organoids.