ER Stress and Lipid Imbalance Drive Diabetic Embryonic Cardiomyopathy in an Organoid Model of Human Heart Development

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2024 Feb 9

PMID 38335962

Authors

Aleksandra Kostina

Yonatan R Lewis-Israeli

Mishref Abdelhamid

Mitchell A Gabalski

Artem Kiselev

Brett D Volmert

Haley Lankerd

Amanda R Huang

Aaron H Wasserman

Todd Lydic

Christina Chan

Sangbum Park

Isoken Olomu

Aitor Aguirre

Affiliations

Soon will be listed here.

Abstract

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.

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References

Lewis-Israeli Y, Wasserman A, Gabalski M, Volmert B, Ming Y, Ball K . Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease. Nat Commun. 2021; 12(1):5142. PMC: 8390749. DOI: 10.1038/s41467-021-25329-5. View

Hofbauer P, Jahnel S, Papai N, Giesshammer M, Deyett A, Schmidt C . Cardioids reveal self-organizing principles of human cardiogenesis. Cell. 2021; 184(12):3299-3317.e22. DOI: 10.1016/j.cell.2021.04.034. View

Zhang Q, Schepis A, Huang H, Yang J, Ma W, Torra J . Designing a Green Fluorogenic Protease Reporter by Flipping a Beta Strand of GFP for Imaging Apoptosis in Animals. J Am Chem Soc. 2019; 141(11):4526-4530. PMC: 6486793. DOI: 10.1021/jacs.8b13042. View

Lehtoranta L, Vuolteenaho O, Laine V, Koskinen A, Soukka H, Kyto V . Maternal hyperglycemia leads to fetal cardiac hyperplasia and dysfunction in a rat model. Am J Physiol Endocrinol Metab. 2013; 305(5):E611-9. DOI: 10.1152/ajpendo.00043.2013. View

Cui X, Zhang Y, Lu Y, Xiang M . ROS and Endoplasmic Reticulum Stress in Pulmonary Disease. Front Pharmacol. 2022; 13:879204. PMC: 9086276. DOI: 10.3389/fphar.2022.879204. View

Kumar S, Dheen S, Tay S . Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development. Cardiovasc Diabetol. 2007; 6:34. PMC: 2176054. DOI: 10.1186/1475-2840-6-34. View

Lane T, Flam B, Lockey R, Kolliputi N . TXNIP shuttling: missing link between oxidative stress and inflammasome activation. Front Physiol. 2013; 4:50. PMC: 3604629. DOI: 10.3389/fphys.2013.00050. View

Niderla-Bielinska J, Jankowska-Steifer E, Flaht-Zabost A, Gula G, Czarnowska E, Ratajska A . Proepicardium: Current Understanding of its Structure, Induction, and Fate. Anat Rec (Hoboken). 2018; 302(6):893-903. DOI: 10.1002/ar.24028. View

Zhong J, Xu C, Gabbay-Benziv R, Lin X, Yang P . Superoxide dismutase 2 overexpression alleviates maternal diabetes-induced neural tube defects, restores mitochondrial function and suppresses cellular stress in diabetic embryopathy. Free Radic Biol Med. 2016; 96:234-44. PMC: 4912469. DOI: 10.1016/j.freeradbiomed.2016.04.030. View

10.

Al-Biltagi M, El Razaky O, El Amrousy D . Cardiac changes in infants of diabetic mothers. World J Diabetes. 2021; 12(8):1233-1247. PMC: 8394229. DOI: 10.4239/wjd.v12.i8.1233. View

11.

Wu Y, Reece E, Zhong J, Dong D, Shen W, Harman C . Type 2 diabetes mellitus induces congenital heart defects in murine embryos by increasing oxidative stress, endoplasmic reticulum stress, and apoptosis. Am J Obstet Gynecol. 2016; 215(3):366.e1-366.e10. PMC: 5260663. DOI: 10.1016/j.ajog.2016.03.036. View

12.

Hamlin R, Altschuld R . Extrapolation from mouse to man. Circ Cardiovasc Imaging. 2011; 4(1):2-4. DOI: 10.1161/CIRCIMAGING.110.961979. View

13.

Volmert B, Kiselev A, Juhong A, Wang F, Riggs A, Kostina A . A patterned human primitive heart organoid model generated by pluripotent stem cell self-organization. Nat Commun. 2023; 14(1):8245. PMC: 10716495. DOI: 10.1038/s41467-023-43999-1. View

14.

Asp M, Giacomello S, Larsson L, Wu C, Furth D, Qian X . A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart. Cell. 2019; 179(7):1647-1660.e19. DOI: 10.1016/j.cell.2019.11.025. View

15.

Mukwevho E, Ferreira Z, Ayeleso A . Potential role of sulfur-containing antioxidant systems in highly oxidative environments. Molecules. 2014; 19(12):19376-89. PMC: 6271769. DOI: 10.3390/molecules191219376. View

16.

Guemes M, Rahman S, Hussain K . What is a normal blood glucose?. Arch Dis Child. 2015; 101(6):569-574. DOI: 10.1136/archdischild-2015-308336. View

17.

Hollien J, Lin J, Li H, Stevens N, Walter P, Weissman J . Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol. 2009; 186(3):323-31. PMC: 2728407. DOI: 10.1083/jcb.200903014. View

18.

Baseler W, Dabkowski E, Jagannathan R, Thapa D, Nichols C, Shepherd D . Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase. Am J Physiol Regul Integr Comp Physiol. 2013; 304(7):R553-65. PMC: 3627941. DOI: 10.1152/ajpregu.00249.2012. View

19.

Volmer R, van der Ploeg K, Ron D . Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc Natl Acad Sci U S A. 2013; 110(12):4628-33. PMC: 3606975. DOI: 10.1073/pnas.1217611110. View

20.

Gandhi J, Zhang X, Maidman J . Fetal cardiac hypertrophy and cardiac function in diabetic pregnancies. Am J Obstet Gynecol. 1995; 173(4):1132-6. DOI: 10.1016/0002-9378(95)91339-4. View