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CD39+ Fibroblasts Enhance Myofibroblast Activation by Promoting IL-11 Secretion in Hypertrophic Scars

  • Author Footnotes
    4 These authors contributed equally to this work.
    Xin Huang
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Author Footnotes
    4 These authors contributed equally to this work.
    Shuchen Gu
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Author Footnotes
    4 These authors contributed equally to this work.
    Caiyue Liu
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Liang Zhang
    Affiliations
    Shanghai Institutes for Biological Sciences, Changzheng Hospital Joint Center for Translational Research, Institutes for Translational Research (CAS-SMMU), Shanghai, China
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  • Zewei Zhang
    Affiliations
    Department of Plastic and Reconstructive Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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  • Yixuan Zhao
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Yimin Khoong
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Haizhou Li
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Yashan Gao
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Yunhan Liu
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Zi Wang
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Danyang Zhao
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Qingfeng Li
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Tao Zan
    Correspondence
    Correspondcence: Tao Zan, Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai 200011, China.
    Affiliations
    Department of Plastic and Reconstructive Surgery, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    Search for articles by this author
  • Author Footnotes
    4 These authors contributed equally to this work.
Published:September 16, 2021DOI:https://doi.org/10.1016/j.jid.2021.07.181
      Fibroblasts (Fbs) are critical to hypertrophic scar (HTS) formation and were recently shown to be highly heterogeneous. However, Fb heterogeneity in HTSs has not been fully elucidated. In this study, we observed an increased fraction of CD39+ Fbs in HTS after screening four Fb subtypes (CD26+, CD36+, FAP+, and CD39+). CD39+ Fbs, enriched in the upper dermis, were positively correlated with scar severity. The transcriptional analysis of CD39+ and CD39 Fbs sorted from HTS revealed that IL-11 was more highly expressed in CD39+ Fbs. We then showed that IL-11 was upregulated in HTSs and that its expression was induced by TGFβ1 in vitro. TGFβ1 also stimulated the expression of CD39 at the transcriptional and protein levels, mediating the maintenance of the CD39+ phenotype. Furthermore, IL-11 facilitated myofibroblast activation and extracellular matrix production in both CD39+ and CD39 Fbs. Interestingly, CD39+ Fbs secreted more IL-11 on TGFβ1 treatment and were less responsive to IL-11 than CD39 Fbs. Notably, a CD39 inhibitor effectively reduced stretch-induced scar formation and attenuated bleomycin-induced skin fibrosis, suggesting an antiscarring approach by targeting CD39+ Fbs.

      Graphical abstract

      Abbreviations:

      αSMA (α-smooth muscle actin), DN (dermal nodule), ECM (extracellular matrix), Fb (fibroblast), HTS (hypertrophic scar), MyoFb (myofibrobalst), NS (normal skin), UD (upper dermis)
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