ER stress and lipid imbalance drive diabetic embryonic cardiomyopathy in an organoid model of human heart development.

Congenital heart defects are the most prevalent human birth defects, and their incidence is exacerbated by maternal health conditions, such as diabetes during the first trimester (pregestational diabetes). Our understanding of the pathology of these disorders is hindered by a lack of human models and the inaccessibility of embryonic tissue. Using an advanced human heart organoid system, we simulated embryonic heart development under pregestational diabetes-like conditions. These organoids developed pathophysiological features observed in mouse and human studies before, including ROS-mediated stress and cardiomyocyte hypertrophy. scRNA-seq revealed cardiac cell-type-specific dysfunction affecting epicardial and cardiomyocyte populations and alterations in the endoplasmic reticulum and very-long-chain fatty acid lipid metabolism. Imaging and lipidomics confirmed these findings and showed that dyslipidemia was linked to fatty acid desaturase 2 mRNA decay dependent on IRE1-RIDD signaling. Targeting IRE1 or restoring lipid levels partially reversed the effects of pregestational diabetes, offering potential preventive and therapeutic strategies in humans.

ER stress and lipid imbalance drive embryonic cardiomyopathy in a human heart organoid model of pregestational diabetes.

Congenital heart defects constitute the most common birth defect in humans, affecting approximately 1% of all live births. The incidence of congenital heart defects is exacerbated by maternal conditions, such as diabetes during the first trimester. Our ability to mechanistically understand these disorders is severely limited by the lack of human models and the inaccessibility to human tissue at relevant stages. Here, we used an advanced human heart organoid model that recapitulates complex aspects of heart development during the first trimester to model the effects of pregestational diabetes in the human embryonic heart. We observed that heart organoids in diabetic conditions develop pathophysiological hallmarks like those previously reported in mouse and human studies, including ROS-mediated stress and cardiomyocyte hypertrophy, among others. Single cell RNA-seq revealed cardiac cell type specific-dysfunction affecting epicardial and cardiomyocyte populations, and suggested alterations in endoplasmic reticulum function and very long chain fatty acid lipid metabolism. Confocal imaging and LC-MS lipidomics confirmed our observations and showed that dyslipidemia was mediated by fatty acid desaturase 2 (FADS2) mRNA decay dependent on IRE1-RIDD signaling. We also found that the effects of pregestational diabetes could be reversed to a significant extent using drug interventions targeting either IRE1 or restoring healthy lipid levels within organoids, opening the door to new preventative and therapeutic strategies in humans.