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

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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.

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Acknowledgements

We sincerely acknowledge Dr. Ulrich Hofmann at University Clinic Halle (Germany) and Dr. Maarten Hulsmans at Harvard Medical School for their tremendous contribution to this project. We thank Li Yang, Rui Yang, Fei Wang, Jian Meng and the BIOPIC FACS facility for technical help.

Funding

This work is supported by the R&D Program of Beijing Municipal Education commission (KJZD20191002301), CAMS Initiative for Innovative Medicine (2017-I2M-003, 2016-I2M-015), the National Natural Science Foundation of China (31601063), SLS-Qidong Innovation Fund and Beijing Advanced Innovation Centre for Genomics at Peking University.

Author information

Author notes

  1. Man Rao, Xiliang Wang and Guangran Guo contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, PUMC, 167 Beilishi Road, Xicheng District, Beijing, 100037, China

    Man Rao, Guangran Guo, Shi Chen, Kai Chen, Liang Chen, Xiao Chen, Shengshou Hu & Jiangping Song

  2. National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, General Hospital of Chinese PLA, Beijing, 100039, China

    Man Rao & Pengbin Yin

  3. BIOPIC and School of Life Sciences, Peking University, No. 5 Yiheyuan Road, Haidian District, Beijing, 100871, China

    Xiliang Wang, Li Wang, Zemin Zhang & Xueda Hu

  4. Analytical Biosciences Limited, Beijing, 100084, China

    Xiliang Wang & Xueda Hu

  5. Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China

    Guangran Guo

  6. Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, 100871, China

    Zemin Zhang

  7. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China

    Zemin Zhang

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  1. Man Rao
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  6. Pengbin Yin
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  7. Kai Chen
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  8. Liang Chen
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  9. Zemin Zhang
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  11. Xueda Hu
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  12. Shengshou Hu
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  13. Jiangping Song
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Contributions

MR, GG, XH, SH, and JS designed the study, XH, SH, and JS supervised the study. MR, GG, LW, and XH performed the experiment. XW, MR, GG, and XH analyzed the data. GG and SC collected clinical samples and clinical data. MR, PY, XW, GG, and XH wrote the manuscript. ZZ, PY, XH, SH, and JS made revisions. XH, SH, and JS provided funding. All authors read the manuscript and approved it before submission.

Corresponding authors

Correspondence to Xueda Hu, Shengshou Hu or Jiangping Song.

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The authors declared that they have no conflict of interest.

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Rao, M., Wang, X., Guo, G. et al. Resolving the intertwining of inflammation and fibrosis in human heart failure at single-cell level. Basic Res Cardiol 116, 55 (2021). https://doi.org/10.1007/s00395-021-00897-1

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  • DOI: https://doi.org/10.1007/s00395-021-00897-1

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