# Neural Organoids Protect Engineered Heart Tissues From Glucolipotoxicity by Transferring Versican in a Co‐Culture System

## TL;DR

Neural organoids protect heart tissues from harmful glucose and fat levels by transferring a protein called versican.

## Contribution

A co-culture system revealed that neural organoids transfer versican to heart tissues, reducing glucolipotoxicity.

## Key findings

- Neural organoids significantly reduce glucolipotoxicity in engineered heart tissues.
- Versican, a matrix protein, is secreted by neural organoids and absorbed by heart tissues under high-glucose/fatty acid conditions.
- Recombinant versican and its overexpression in mice ameliorate cardiac dysfunction caused by metabolic disorders.

## Abstract

Metabolic disorders could cause dysregulated glucose and lipid at the systemic level, but how inter‐tissue/organ communications contribute to glucolipotoxicity is difficult to dissect in animal models. To solve this problem, myocardium and nerve tissues were modelled by 3D engineered heart tissues (EHTs) and neural organoids (NOs), which were co‐cultured in a generalised medium with normal or elevated glucose/fatty acid contents. Morphology, gene expression, cell death and functional assessments detected no apparent alterations of EHTs and NOs in co‐culture under normal conditions. By contrast, NOs significantly ameliorated glucolipotoxicity in EHTs. Transcriptomic and protein secretion assays identified the extracellular matrix protein versican as a key molecule that was transferred from NOs into EHTs in the high‐glucose/fatty acid condition. Recombinant versican protein treatment was sufficient to reduce glucolipotoxicity in EHTs. Adeno‐associated virus‐delivered versican overexpression was sufficient to ameliorate cardiac dysfunction in a murine model of diabetic cardiomyopathy. These data provide the proof‐of‐concept evidence that inter‐tissue/organ communications exist in the co‐culture of engineered tissues and organoids, which could be systemically studied to explore potential pathological mechanisms and therapeutic strategies for multi‐organ diseases in vitro.

In this study, Bai et al. established a co‐culture system between neural organoids (NOs) and engineered heart tissues (EHTs) and demonstrated that NOs could secrete versican, which was absorbed by EHTs to ameliorate glucolipotoxicity.