Resolving the intertwining of inflammation and fibrosis in human heart failure at single-cell level.

Abstract

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.

• Authors: Man Rao, Xiliang Wang, Guangran Guo, Li Wang, Shi Chen, Pengbin Yin, Kai Chen, Liang Chen, Zemin Zhang, Xiao Chen, Xueda Hu, Shengshou Hu, Jiangping Song
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 116 Issue 1 Pg. 55 (10 03 2021) ISSN: 1435-1803 [Electronic] Germany
• PMID: 34601654 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• AEBP1 protein, human
• Repressor Proteins
• Carboxypeptidases

Topics

• CD8-Positive T-Lymphocytes
• Carboxypeptidases
• Cardiomyopathy, Dilated (genetics, pathology)
• Fibrosis
• Heart Failure (pathology)
• Humans
• Inflammation (pathology)
• Myocardium (pathology)
• Repressor Proteins