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

Autor: Kostina A; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA., Lewis-Israeli YR; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA., Abdelhamid M; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI, USA., Gabalski MA; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA., Volmert BD; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA., Lankerd H; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA., Huang AR; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA., Wasserman AH; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA., Lydic T; Department of Physiology, Michigan State University, MI, USA., Chan C; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA.; Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA., Olomu I; Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI, USA., Aguirre A; Division of Developmental and Stem Cell Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.; Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Jun 08. Date of Electronic Publication: 2023 Jun 08.
DOI: 10.1101/2023.06.07.544081
Abstrakt: 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.
Databáze: MEDLINE