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Stem cell antigen-1+cell-derived fibroblasts are crucial for cardiac fibrosis during heart failure

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Abstract

Aims

Mesenchymal stem cells (MSCs) present in the heart cannot differentiate into cardiomyocytes, but may play a role in pathological conditions. Therefore, the aim of this study was to scrutinise the role and mechanism of MSC differentiation in vivo during heart failure.

Methods and Results

We performed single-cell RNA sequencing of total non-cardiomyocytes from murine and adult human hearts. By analysing the transcriptomes of single cells, we illustrated the dynamics of the cell landscape during the progression of heart hypertrophy, including those of stem cell antigen-1 (Sca1)+ stem/progenitor cells and fibroblasts. By combining genetic lineage tracing and bone marrow transplantation models, we demonstrated that non-bone marrow-derived Sca1+ cells give rise to fibroblasts. Interestingly, partial depletion of Sca1+ cells alleviated the severity of myocardial fibrosis and led to a significant improvement in cardiac function in Sca1-CreERT2;Rosa26-eGFP-DTA mice. Similar non-cardiomyocyte cell composition and heterogeneity were observed in human patients with heart failure. Mechanistically, our study revealed that Sca1+ cells can transform into fibroblasts and affect the severity of fibrosis through the Wnt4-Pdgfra pathway.

Conclusions

Our study describes the cellular landscape of hypertrophic hearts and reveals that fibroblasts derived from Sca1+ cells with a non-bone marrow source largely account for cardiac fibrosis. These findings provide novel insights into the pathogenesis of cardiac fibrosis and have potential therapeutic implications for heart failure.

Graphical abstract

Non-bone marrow-derived Sca1+ cells differentiate into fibroblasts involved in cardiac fibrosis via Wnt4-PDGFRα pathway.

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Data availability

The single-cell RNA sequencing data have been deposited in the Gene Expression Omnibus under accession number GSE198833 and GSE222144. The data underlying this article will be shared on reasonable request to the corresponding author.

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Acknowledgements

We are grateful to Ms. Chao Bi and Ms. Xiaoli Hong at the Core Facilities, Zhejiang University School of Medicine for technical assistance in confocal microscopy.

Funding

This work is supported by National Natural Science Foundation of China (82030008, 82270409, 31830039), Natural Science Foundation of Zhejiang Province (LQ23H020006), Science and technology Project of Zhejiang Province (2023C03087).

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  1. Tingting Tao and Luping Du contributed equally.

Authors and Affiliations

  1. Department of Cardiovascular Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China

    Tingting Tao, Peng Teng, Haige Zhao & Liang Ma

  2. Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China

    Luping Du, Yan Guo, Xuyang Wang, Yanhua Hu & Qingbo Xu

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  1. Tingting Tao
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Contributions

All authors contributed to the study conception and design. Material preparation was performed by TT, YG, XW. Data collection was performed by PT, HZ, LM. Analysis was performed by LD. The first draft of the manuscript was written by TT, LD, YH, QX and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qingbo Xu or Liang Ma.

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

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Research Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine (approval no. IIT20210018B-R2).

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Tao, T., Du, L., Teng, P. et al. Stem cell antigen-1+cell-derived fibroblasts are crucial for cardiac fibrosis during heart failure. Cell. Mol. Life Sci. 80, 300 (2023). https://doi.org/10.1007/s00018-023-04957-8

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