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 an...

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Veröffentlicht in:Stem cell reports 2024-03, Vol.19 (3), p.317-330
Hauptverfasser: Kostina, Aleksandra, Lewis-Israeli, Yonatan R., Abdelhamid, Mishref, Gabalski, Mitchell A., Kiselev, Artem, Volmert, Brett D., Lankerd, Haley, Huang, Amanda R., Wasserman, Aaron H., Lydic, Todd, Chan, Christina, Park, Sangbum, Olomu, Isoken, Aguirre, Aitor
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •Heart organoids to investigate pregestational diabetes-congenital heart defects•scRNA-seq revealed significant transcriptomic alterations in cardiac cell types•ER stress and disrupted lipid metabolism were significant features of PGD-CHD•Strategies reducing ER stress/restoring normal lipid balance were cardioprotective Kostina et al. investigate how exposure to diabetes during early embryonic development affects the human heart in an innovative hPSC-derived heart organoid model. The authors discover that exposure to diabetes triggers ER stress and VLCFA dyslipidemia in the embryonic heart. Restoration of ER homeostasis and/or VLCFA levels using small molecules provided a significant degree of cardioprotection, suggesting new therapeutic alternatives.
ISSN:2213-6711
2213-6711
DOI:10.1016/j.stemcr.2024.01.003