Organoid model for the study of diabetic embryonic cardiomyopathy
2024
Michigan State University, East Lansing, USA
Congenital heart defects are the most common birth defects in humans, and their incidence is exacerbated by maternal health disorders such as diabetes in the first trimester (gestational diabetes). The understanding of the pathology of these disorders is hampered by a lack of human models and the inaccessibility of embryonic tissue. Here, using an advanced human cardiac organoid system, embryonic heart development was simulated under conditions resembling gestational diabetes. These organoids developed pathophysiological features previously observed in human studies, including ROS-mediated stress and cardiomyocyte hypertrophy. scRNA-seq revealed heart cell type-specific dysfunction affecting epicardial and cardiomyocyte populations, as well as alterations in endoplasmic reticulum and very-long-chain fatty acid lipid metabolism. Imaging and lipidomics confirmed these findings and showed that dyslipidaemia is associated with IRE1-RIDD signalling-dependent mRNA decay of fatty acid desaturase 2. By targeting IRE1 or restoring lipid levels, the effects of gestational diabetes could be partially reversed, opening up potential preventive and therapeutic strategies for humans.
ER stress and lipid imbalance drive diabetic embryonic cardiomyopathy in an organoid model of human heart development
Aitor Aguirre
Added on: 03-26-2024
[1] https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(24)00006-7?emci=ac800d7f-ccdf-ee11-85fb-002248223794&emdi=47a541bd-dddf-ee11-85fb-002248223794&ceid=2015591
