# Modeling embryonic heart vascular plexus development and sympathetic innervation on a human heart organoid

## TL;DR

Researchers created a human heart organoid that models heart vascular and nerve development, offering a new tool to study heart formation and function.

## Contribution

A self-organized human heart organoid that models vascular plexus and sympathetic innervation development.

## Key findings

- EMOs develop a functional coronary-like vascular plexus through VEGF and PDGFβ signaling.
- Innervated EMOs show integrated neurovascular organization and respond to nicotine.
- The model mirrors in vivo epicardial-to-mesenchymal transition and cell lineage development.

## Abstract

Coronary vascularization and sympathetic innervation are tightly coordinated during heart development and are essential for normal cardiac function. Here, we present a self-organized human iPSC-derived epicardium-myocardium organoid (EMO) that mimics heart vascular plexus development and integration with myocardium sympathetic innervation. Through the modulation of VEGF and PDGFβ signaling, EMOs develop a functional, self-generated coronary-like vascular plexus (V-EMOs). and display active epicardial-to-mesenchymal transition trajectories into fibroblast, mural, and vascular cell lineages, mirroring in vivo processes. Assembly of these vascularized EMOs with human iPSC-derived sympathetic neuron spheroids yields innervated EMOs exhibiting integrated neurovascular organization and functional responses to nicotine stimulation (iV-EMOs). This modular, developmentally guided organoid system features coordinated human cardiac, vascular, and neural development, providing a physiologically relevant platform for studying heart morphogenesis, neurovascular interactions, and regenerative therapeutic strategies.

•hPSC-derived EMOs recreate key stages of human heart morphogenesis and architecture•EMOs show a functional self-generated and organized coronary-like vascular plexus•VEGF-PDGFβ regulates epicardial-derived cells specification and spatial patterning•Sympathetic innervated EMOs exhibit physiological responses to nicotine stimulation

hPSC-derived EMOs recreate key stages of human heart morphogenesis and architecture

EMOs show a functional self-generated and organized coronary-like vascular plexus

VEGF-PDGFβ regulates epicardial-derived cells specification and spatial patterning

Sympathetic innervated EMOs exhibit physiological responses to nicotine stimulation

Branco et al. describe a functional vascularized and innervated heart organoid that recreates, in a stepwise manner, the temporal and spatial development of the human heart. The self-generated cues present in this model support epicardial-derived cells specification and the establishment of a self-organized coronary-like vascular plexus, interconnected with a sympathetic neuronal network.