Single-cell Transcriptomic Profiling Unveils Dysregulation of Cardiac Progenitor Cells and Cardiomyocytes in a Mouse Model of Maternal Hyperglycemia

Overview

Journal Commun Biol

Specialty Biology

Date 2022 Aug 15

PMID 35970860

Authors

Sathiyanarayanan Manivannan

Corrin Mansfield

Xinmin Zhang

Karthik M Kodigepalli

Uddalak Majumdar

Vidu Garg

Madhumita Basu

Affiliations

Soon will be listed here.

Abstract

Congenital heart disease (CHD) is the most prevalent birth defect, often linked to genetic variations, environmental exposures, or combination of both. Epidemiological studies reveal that maternal pregestational diabetes is associated with ~5-fold higher risk of CHD in the offspring; however, the causal mechanisms affecting cardiac gene-regulatory-network (GRN) during early embryonic development remain poorly understood. In this study, we utilize an established murine model of pregestational diabetes to uncover the transcriptional responses in key cell-types of the developing heart exposed to maternal hyperglycemia (matHG). Here we show that matHG elicits diverse cellular responses in E9.5 and E11.5 embryonic hearts compared to non-diabetic hearts by single-cell RNA-sequencing. Through differential-gene-expression and cellular trajectory analyses, we identify perturbations in genes, predominantly affecting Isl1 second heart field progenitors and Tnnt2 cardiomyocytes with matHG. Using cell-fate mapping analysis in Isl1-lineage descendants, we demonstrate that matHG impairs cardiomyocyte differentiation and alters the expression of lineage-specifying cardiac genes. Finally, our work reveals matHG-mediated transcriptional changes in second heart field lineage that elevate CHD risk by perturbing Isl1-GRN during cardiomyocyte differentiation. Gene-environment interaction studies targeting the Isl1-GRN in cardiac progenitor cells will have a broader impact on understanding the mechanisms of matHG-induced risk of CHD associated with diabetic pregnancies.

Citing Articles

Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease.

Choudhury T, Greskovich S, Girard H, Rao A, Budhathoki Y, Cameron E JCI Insight. 2024; 9(23).

PMID: 39437002 PMC: 11623948. DOI: 10.1172/jci.insight.183516.

A review of single-cell transcriptomics and epigenomics studies in maternal and child health.

Shu C, Street K, Breton C, Bastain T, Wilson M Epigenomics. 2024; 16(10):775-793.

PMID: 38709139 PMC: 11318716. DOI: 10.1080/17501911.2024.2343276.

Maternal Pre-Existing Diabetes: A Non-Inherited Risk Factor for Congenital Cardiopathies.

Ibrahim S, Gaborit B, Lenoir M, Collod-Beroud G, Stefanovic S Int J Mol Sci. 2023; 24(22).

PMID: 38003449 PMC: 10671602. DOI: 10.3390/ijms242216258.

Research Progress of Maternal Metabolism on Cardiac Development and Function in Offspring.

Ren Z, Luo S, Cui J, Tang Y, Huang H, Ding G Nutrients. 2023; 15(15).

PMID: 37571325 PMC: 10420869. DOI: 10.3390/nu15153388.

Long-term outcomes and potential mechanisms of offspring exposed to intrauterine hyperglycemia.

Yan Y, Feng C, Yu D, Tian S, Zhou Y, Huang Y Front Nutr. 2023; 10:1067282.

PMID: 37255932 PMC: 10226394. DOI: 10.3389/fnut.2023.1067282.

References

DeLaughter D, Bick A, Wakimoto H, McKean D, Gorham J, Kathiriya I . Single-Cell Resolution of Temporal Gene Expression during Heart Development. Dev Cell. 2016; 39(4):480-490. PMC: 5198784. DOI: 10.1016/j.devcel.2016.10.001. View

Quijada P, Trembley M, Small E . The Role of the Epicardium During Heart Development and Repair. Circ Res. 2020; 126(3):377-394. PMC: 7000171. DOI: 10.1161/CIRCRESAHA.119.315857. View

Nees S, Chung W . The genetics of isolated congenital heart disease. Am J Med Genet C Semin Med Genet. 2019; 184(1):97-106. PMC: 8211463. DOI: 10.1002/ajmg.c.31763. View

Soldatov R, Kaucka M, Kastriti M, Petersen J, Chontorotzea T, Englmaier L . Spatiotemporal structure of cell fate decisions in murine neural crest. Science. 2019; 364(6444). DOI: 10.1126/science.aas9536. View

Benson D, Silberbach G, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S . Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest. 1999; 104(11):1567-73. PMC: 409866. DOI: 10.1172/JCI8154. View

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

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

Zhuang S, Zhang Q, Zhuang T, Evans S, Liang X, Sun Y . Expression of Isl1 during mouse development. Gene Expr Patterns. 2013; 13(8):407-12. PMC: 4134129. DOI: 10.1016/j.gep.2013.07.001. View

Zhao M, Diao J, Huang P, Li J, Li Y, Yang Y . Association of Maternal Diabetes Mellitus and Polymorphisms of the Gene in Children with Congenital Heart Disease: A Single Centre-Based Case-Control Study. J Diabetes Res. 2020; 2020:3854630. PMC: 7533784. DOI: 10.1155/2020/3854630. View

10.

Cai C, Liang X, Shi Y, Chu P, Pfaff S, Chen J . Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003; 5(6):877-89. PMC: 5578462. DOI: 10.1016/s1534-5807(03)00363-0. View

11.

Zhou L, Liu J, Olson P, Zhang K, Wynne J, Xie L . Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation. J Mol Cell Cardiol. 2015; 85:1-12. PMC: 4530064. DOI: 10.1016/j.yjmcc.2015.05.005. View

12.

Poelmann R, Lie-Venema H, Gittenberger-de Groot A . The role of the epicardium and neural crest as extracardiac contributors to coronary vascular development. Tex Heart Inst J. 2002; 29(4):255-61. PMC: 140287. View

13.

de Boer B, van den Berg G, de Boer P, Moorman A, Ruijter J . Growth of the developing mouse heart: an interactive qualitative and quantitative 3D atlas. Dev Biol. 2012; 368(2):203-13. DOI: 10.1016/j.ydbio.2012.05.001. View

14.

Theodoris C, Li M, White M, Liu L, He D, Pollard K . Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency. Cell. 2015; 160(6):1072-86. PMC: 4359747. DOI: 10.1016/j.cell.2015.02.035. View

15.

Savolainen S, Foley J, Elmore S . Histology atlas of the developing mouse heart with emphasis on E11.5 to E18.5. Toxicol Pathol. 2009; 37(4):395-414. PMC: 2773446. DOI: 10.1177/0192623309335060. View

16.

Hoang T, Goldmuntz E, Roberts A, Chung W, Kline J, Deanfield J . The Congenital Heart Disease Genetic Network Study: Cohort description. PLoS One. 2018; 13(1):e0191319. PMC: 5774789. DOI: 10.1371/journal.pone.0191319. View

17.

Moretti A, Lam J, Evans S, Laugwitz K . Biology of Isl1+ cardiac progenitor cells in development and disease. Cell Mol Life Sci. 2007; 64(6):674-82. PMC: 11138427. DOI: 10.1007/s00018-007-6520-5. View

18.

Solmonson A, Faubert B, Gu W, Rao A, Cowdin M, Menendez-Montes I . Compartmentalized metabolism supports midgestation mammalian development. Nature. 2022; 604(7905):349-353. PMC: 9007737. DOI: 10.1038/s41586-022-04557-9. View

19.

Schott J, Benson D, Basson C, Pease W, Silberbach G, Moak J . Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science. 1998; 281(5373):108-11. DOI: 10.1126/science.281.5373.108. View

20.

Feng Q, Song W, Lu X, Hamilton J, Lei M, Peng T . Development of heart failure and congenital septal defects in mice lacking endothelial nitric oxide synthase. Circulation. 2002; 106(7):873-9. DOI: 10.1161/01.cir.0000024114.82981.ea. View