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bioRxiv · 10.1101/2025.01.10.632325

Recreating coronary vascularization and sympathetic innervation of myocardium on a human pluripotent stem cell-derived heart organoid

Branco, M.·Nunes, M. M.·Rayagra, A. L.·Tenreiro, M.·Cabral, J. S.·Diogo, M. M.
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Abstract

Coronary vascularization and sympathetic innervation of the myocardium is a concomitant event during embryonic heart development and both systems are crucial to ensure normal adult heart function. Here we describe a self-organized hiPSC-derived heart organoid that recreates both the coronary vascular plexus and the sympathetic neuronal network of the ventricle myocardium, with a physiologically relevant in-vivo-like structural organization and function. Through modulation of PDGF-{beta} and VEGF signalling pathways, we attained a heart organoid that incorporates 1) an external epicardial layer (mesothelium) of DACH1, NR2F2 and WT1 positive cells, 2) a sub-epicardial space from where a functional primary coronary vascular plexus of CD31+/DACH1+ cells emerge, 3) a compact myocardial region adjacent to the epicardium, enriched in proliferative cardiomyocytes and ECM deposition, and 4) a sympathetic neuronal network that controls heart organoid contraction. Therefore, the human heart organoid described herein, is a unique model to study new regenerative medicine-based approaches to restore innervation and promote re-vascularization in adult heart after ischemic events and to perform adult and developmental cardiotoxicity studies.

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Branco, M., Nunes, M. M., Rayagra, A. L., Tenreiro, M., Cabral, J. S., Diogo, M. M.. 2025-01-10. Recreating coronary vascularization and sympathetic innervation of myocardium on a human pluripotent stem cell-derived heart organoid. https://doi.org/10.1101/2025.01.10.632325

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