Summary

Inflammation and fibrosis are intertwined mechanisms fundamentally involved in heart failure. Detailed deciphering gene expression perturbations and cell-cell interactions of leukocytes and non-myocytes is required to understand cell-type-specific pathology in the failing human myocardium. To this end, we performed single-cell RNA sequencing and single T cell receptor sequencing of 200,615 cells in both human dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) hearts. We sampled both lesion and mild-lesion tissues from each heart to sequentially capture cellular and molecular alterations to different extents of cardiac fibrosis. By which, left (lesion) and right ventricle (mild-lesion) for DCM hearts were harvest while infarcted (lesion) and non-infarcted area (mild-lesion) were dissected from ICM hearts. A novel transcription factor AEBP1 was identified as a crucial cardiac fibrosis regulator in ACTA2+ myofibroblasts. Within fibrotic myocardium, an infiltration of a considerable number of leukocytes was witnessed, especially cytotoxic and exhausted CD8+ T cells and pro-inflammatory CD4+ T cells. Furthermore, a subset of tissue-resident macrophage, CXCL8hiCCR2+HLA-DRhi macrophage was particularly identified in severely fibrotic area, which interacted with activated endothelial cell via DARC, that potentially facilitate leukocyte recruitment and infiltration in human heart failure.

Overall design

we performed single cell RNA sequencing (scRNA-seq) in both normal and failed human heart. CD45- cells in the myocardium and immune cells (CD45+ cells) were isolated from myocardium and corresponding peripheral blood were sorted for scRNA-seq. Our findings were also validated with bulk RNAseq.

Contributors

Man Rao†, Xiliang Wang†, Guangran Guo†, Xueda Hu✉️, Shengshou Hu✉️, Jiangping Song✉️

Contact

To be supplemented.