Single-cell RNA-seq of heart reveals intercellular communication drivers of myocardial fibrosis in diabetic cardiomyopathy
- Soochow University, China
- Nanjing Medical University, China
- Suzhou Polytechnic Institute of Agriculture, China
Abstract
Myocardial fibrosis is the characteristic pathology of diabetes-induced cardiomyopathy. Therefore, an in-depth study of cardiac heterogeneity and cell-to-cell interactions can help elucidate the pathogenesis of diabetic myocardial fibrosis and identify treatment targets for the treatment of this disease. In this study, we investigated intercellular communication drivers of myocardial fibrosis in mouse heart with high-fat-diet (HFD)/streptozotocin (STZ)-induced diabetes at single-cell resolution. Intercellular and protein-protein interaction networks of fibroblasts and macrophages, endothelial cells, as well as fibroblasts and epicardial cells revealed critical changes in ligand-receptor interactions such as Pdgf(s)-Pdgfra and Efemp1-Egfr, which promote the development of a profibrotic microenvironment during the progression of and confirmed that the specific inhibition of the Pdgfra axis could significantly improve diabetic myocardial fibrosis. We also identified phenotypically distinct Hrchi and Postnhi fibroblast subpopulations associated with pathological extracellular matrix remodeling, of which the Hrchi fibroblasts were found to be the most profibrogenic under diabetic conditions. Finally, we validated the role of the Itgb1 hub gene mediated intercellular communication drivers of diabetic myocardial fibrosis in Hrchi fibroblasts, and confirmed the results through AAV9-mediated Itgb1 knockdown in the heart of diabetic mice. In summary, cardiac cell mapping provides novel insights into intercellular communication drivers involved in pathological extracellular matrix remodeling during diabetic myocardial fibrosis.
Data availability
All sequencing data that support this study is available from the Genome Sequence Archive in BIG Data Center (http://bigd.big.ac.cn/) with the accession code CRA007245. The ligand and receptor pairing dataset was obtained from Fantom5 (https://fantom.gsc.riken.jp/5/suppl/Ramilowski_et_al_2015/), as recently described (Ramilowski et al., 2015). Source data files are provided to support CT values of Col1a1 and Col3a1 used for Figure 3G-H. Source data files are provided to support CT values of Itgb1 used for Figure 6H. Source data files are provided to support Table 1 in Figure 3-Figure supplement 5.
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Single-Cell RNA-seq of Heart Reveals Intercellular Communication Drivers of Myocardial Fibrosis in Diabetic MiceCNCB Genome Sequence Archive, CRA007245.
Article and author information
Author details
Funding
Suzhou Science and Technology Development Plan (SKJY 2021038)
- Shigang Qiao
Jiangsu Key Talent Youth Awards in Medicine (QNRC2016219)
- Shigang Qiao
Gusu Health Youth Talent Awards (GSWS2019092)
- Shigang Qiao
Gusu Health Talent Program (GSWS2021068)
- Zhenhao Zhang
Suzhou New District Science and Technology Project (2020Z007)
- Zhenhao Zhang
General Program of Basic Science in Jiangsu Higher Education Institutions (21KJB350017)
- Shudi Yang
the Core Medical Science Subjects in Suzhou (SZXK202131)
- Shudi Yang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was approved by the Ethics Committee of Soochow University and Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University. Reference number: 2022-B23. All mouse were treated in accordance with the National Institutes of Health's Guidelines for the Care and Use of Experimental Animals (NIH publications No. 80-23, revised 1996).
Copyright
© 2023, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single-cell RNA-seq of heart reveals intercellular communication drivers of myocardial fibrosis in diabetic cardiomyopathy
eLife 12:e80479.
https://doi.org/10.7554/eLife.80479
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