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Single-cell transcriptomic identified HIF1A as a target for attenuating acute rejection after heart transplantation

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Abstract

Acute rejection (AR) is an important contributor to graft failure, which remains a leading cause of death after heart transplantation (HTX). The regulation of immune metabolism has become a new hotspot in the development of immunosuppressive drugs. In this study, Increased glucose metabolism of cardiac macrophages was found in patients with AR. To find new therapeutic targets of immune metabolism regulation for AR, CD45+ immune cells extracted from murine isografts, allografts, and untransplanted donor hearts were explored by single-cell RNA sequencing. Total 20 immune cell subtypes were identified among 46,040 cells. The function of immune cells in AR were illustrated simultaneously. Cardiac resident macrophages were substantially replaced by monocytes and proinflammatory macrophages during AR. Monocytes/macrophages in AR allograft were more active in antigen presentation and inflammatory recruitment ability, and glycolysis. Based on transcription factor regulation analysis, we found that the increase of glycolysis in monocytes/macrophages was mainly regulated by HIF1A. Inhibition of HIF1A could alleviate inflammatory cells infiltration in AR. To find out the effect of HIF1A on AR, CD45+ immune cells extracted from allografts after HIF1A inhibitor treatment were explored by single-cell RNA sequencing. HIF1A inhibitor could reduce the antigen presenting ability and pro-inflammatory ability of macrophages, and reduce the infiltration of Cd4+ and Cd8a+ T cells in AR. The expression of Hif1α in AR monocytes/macrophages was regulated by pyruvate kinase 2. Higher expression of HIF1A in macrophages was also detected in human hearts with AR. These indicated HIF1A may serve as a potential target for attenuating AR.

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Availability of data and material

The data that support the findings of this study including scRNA-seq data are available from https://figshare.com/s/11d8b3c99165c5fd8cd3.

Code availability

R scripts for single cell data analysis are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Fund for Distinguished Young Scholars of China (82125004; to JPS) and the National Natural Science Fund for General Program of China (81670376; to JPS).

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Authors and Affiliations

  1. Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China

    Yuan Chang & Shengshou Hu

  2. School of Statistics and Data Science, Nankai University, Tianjin, 300371, China

    Xiangjie Li

  3. The Cardiomyopathy Research Group at Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100000, China

    Yuan Chang, Xiangjie Li, Yiqing Hu, Xiao Chen, Xiumeng Hua, Xuexin Fan, Menghao Tao, Jiangping Song & Shengshou Hu

  4. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China

    Qi Cheng

  5. Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Ministry of Education, National Health Commission, Wuhan, 430000, China

    Qi Cheng

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  10. Shengshou Hu
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Contributions

JPS designed and supervised the study. YC, YQH and XMH performed scRNA-seq. QC performed HTX experiments. XJL was responsible for the analysis of scRNA-seq data. XC, XXF, MHT participated in sample collection and processing. YC and XJL wrote the manuscript draft. JPS and SSH revised the manuscript. All authors read and approved the manuscript. YC, XJL, QC, and YQH contributed equally to this work.

Corresponding author

Correspondence to Jiangping Song.

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Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

The use of human tissue in the present study was approved by the Human Ethics Committee of Fuwai Hospital, Chinese Academy of Medical Sciences (no. 2013-049). Written informed consent was obtained from each patient. This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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Not applicable.

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Chang, Y., Li, X., Cheng, Q. et al. Single-cell transcriptomic identified HIF1A as a target for attenuating acute rejection after heart transplantation. Basic Res Cardiol 116, 64 (2021). https://doi.org/10.1007/s00395-021-00904-5

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  • DOI: https://doi.org/10.1007/s00395-021-00904-5

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