Single-cell transcriptomic profiling unveils dysregulation of cardiac progenitor cells and cardiomyocytes in a mouse model of maternal hyperglycemia.
Sathiyanarayanan ManivannanCorrin MansfieldXinmin ZhangKarthik M KodigepalliUddalak MajumdarVidu GargMadhumita BasuPublished in: Communications biology (2022)
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.
Keyphrases
- single cell
- rna seq
- gene expression
- type diabetes
- genome wide
- high throughput
- congenital heart disease
- high glucose
- left ventricular
- pregnancy outcomes
- heart failure
- cell fate
- cardiovascular disease
- mouse model
- birth weight
- dna methylation
- atrial fibrillation
- gestational age
- diabetic rats
- transcription factor
- glycemic control
- high resolution
- copy number
- angiotensin ii
- drug delivery
- body mass index
- risk assessment
- high fat diet
- metabolic syndrome
- binding protein
- human health
- bone marrow
- high density
- mesenchymal stem cells
- network analysis