Myocardial B cells have specific gene expression and predicted interactions in Dilated Cardiomyopathy and Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract

Background: A growing body of evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is minimal data on human myocardial B cells and their biological niche within the heart remains mostly unexplored. Methods: We integrated single-cell and single-nuclei datasets from 45 healthy human hearts, 70 hearts with dilated cardiomyopathy (DCM), and 8 hearts with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Interactions between B cells and other cell types were investigated using the CellChat Package. Differential gene expression analysis comparing B cells across conditions was performed using DESeq2. Pathway analysis was performed using Ingenuity, KEGG, and GO pathways analysis. Results: Out of 1,200,752 nuclei and 49,723 cells, we identified 1,100 B cells, including naive B cells and plasma cells. B cells showed an extensive network of interactions within the healthy myocardium that included outgoing signaling to macrophages, T cells, endothelial cells, and pericytes, and incoming signaling from endothelial cells, pericytes, and fibroblasts. This biological niche relied on both ECM-receptor interactions, cell-cell contact interactions, and paracrine interaction, it changed significantly in the context of cardiomyopathy and had disease-specific features. Differential gene expression analysis showed that in the context of DCM both naive and plasma myocardial B cells upregulated several pathways related to immune activation, including upregulation of oxidative phosphorylation, upregulation of leukocyte extravasation and, in naive B cells, antigen processing and presentation. Conclusions: The human healthy and diseased myocardium contains naive B cells and plasma cells, integrated in a diverse and dynamic biological niche. Naive myocardial-associated B cells likely contribute to the pathogenesis of human dilated cardiomyopathy.

B cell-mediated antigen presentation promotes adverse cardiac remodeling in chronic heart failure

“…A clustering resolution of 0.5 and 0.4 was used for the ICM and STEMI datasets respectively. B cells were identified using known human B cell-specific makers as previously described (Supplementary Table 5) (49). For the larger dataset, B cells were pseudobulked per patient and differential gene expression was performed using DEseq2 controlling for sex and 10x chemistry in the regression model.…”

“…A clustering resolution of 0.5 and 0.4 was used for the ICM and STEMI datasets respectively. B cells were identified using known human B cell-specific makers as previously described (Supplementary Table 5) (43). Subsequent comparative gene analyses and pathway analyses were performed as described above.…”

B cell-mediated antigen presentation promotes adverse cardiac remodeling in chronic heart failure

“…A clustering resolution of 0.5 and 0.4 was used for the ICM and STEMI datasets respectively. B cells were identified using known human B cell-specific makers as previously described (Supplementary Table 4) (49). For the larger dataset, B cells were pseudobulked per patient and differential gene expression was performed using DEseq2 controlling for sex and 10x chemistry in the regression model.…”