Single-Cell RNA-seq of Heart Reveals Intercellular Communication Drivers of Myocardial Fibrosis in Diabetic Mice

Abstract

Diabetes-induced cardiomyopathy is characterized by myocardial fibrosis as a main pathology. In-depth study of cardiac heterogeneity and cell-to-cell interactions will help to reveal the pathogenesis of diabetic myocardial fibrosis and provide potential targets for the treatment of this disease. Here, we insighted into the intercellular communication drivers underlying myocardial fibrosis in mouse heart with high-fat-diet (HFD)/streptozotocin (STZ)-induced diabetes at single-cell resolution. Intercellular and protein-protein interaction networks of fibroblasts and macrophages, endothelial cells, as well as fibroblasts and epicardial cells reveal critical changes in ligand-receptor interactions such as Pdgf(s)-Pdgfra and Efemp1-Egfr, which promote the development of a profibrotic microenvironment during diabetes progression and confirm that specific inhibition of Pdgfra axis can significantly improve diabetic myocardial fibrosis. We further identified the phenotypically distinct Hrchi and Postnhi fibroblast subpopulations that are associated with pathological extracellular matrix remodeling, of which Hrchi fibroblasts are the most profibrogenic under diabetic conditions. Finally, we validated the role of Itgb1 hub gene mediated intercellular communication drivers of diabetic myocardial fibrosis in Hrchi fibroblasts, and confirmed the result by AAV9-mediated Itgb1 knockdown in the heart of diabetic mice. In summary, cardiac cell mapping provides novel insights into intercellular communication drivers underlying pathological extracellular matrix remodeling during diabetic myocardial fibrosis.

Retinal ganglion cell type-specific expression of synuclein family members revealed by scRNA-sequencing

“…The importance of cellular communication networks in disease progression is increasingly recognized 45 - 47 . In the case of ONC, which results in the transection of RGC axons and subsequent RGC death, the changes in cell-cell communication during this process have not been fully explored.…”

Single-cell and spatial heterogeneity landscapes of mature epicardial cells

“…During embryonic development, murine Efemp1 mRNA expression initiates at embryonic day 9.5 in condensing mesenchyme structures and persists throughout development, thus contributing to the formation of bone, cartilage, and various skeletal structures, including the craniofacial, appendicular, and axial skeleton [ 61 ]. Recent studies have elucidated the role of Efemp1 in the progression of myocardial fibrosis in diabetes-induced cardiomyopathy, as well as its association with the prognosis of patients with acute MI [ 62 , 63 ]. However, limited research has explored the relationship between Efemp1 and the epicardium.…”

Translatome analysis reveals microglia and astrocytes to be distinct regulators of inflammation in the hyperacute and acute phases after stroke

“…One advantage of obtaining microglia and astrocyte-enriched translatomes at the same time points is the ability to examine how each cell contributes to pathways. After stroke, the TNF signaling pathway in both microglia and astrocytes has been found to disrupt blood brain barrier function and worsen outcomes (Chen et al, 2019;Li et al, 2022). Because it was enriched in all three gene lists and is important in pro-inflammatory signaling, we chose the KEGG TNF signaling pathway (Kanehisa & Goto, 2000) to highlight the ability of our data to identify unique microglial, astrocyte, and shared gene contributions.…”