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Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair

Author

Listed:
  • Filipa C. Simões

    (University of Oxford
    University of Oxford
    University of Oxford)

  • Thomas J. Cahill

    (University of Oxford
    University of Oxford
    University of Oxford)

  • Amy Kenyon

    (University of Oxford)

  • Daria Gavriouchkina

    (University of Oxford
    Molecular Genetics Unit, Okinawa Institute of Science & Technology)

  • Joaquim M. Vieira

    (University of Oxford
    University of Oxford)

  • Xin Sun

    (University of Oxford
    University of Oxford)

  • Daniela Pezzolla

    (University of Oxford)

  • Christophe Ravaud

    (University of Oxford
    University of Oxford)

  • Eva Masmanian

    (University of Oxford)

  • Michael Weinberger

    (University of Oxford
    University of Oxford)

  • Sarah Mayes

    (University of Oxford
    University of Oxford)

  • Madeleine E. Lemieux

    (Bioinfo)

  • Damien N. Barnette

    (University of Oxford)

  • Mala Gunadasa-Rohling

    (University of Oxford)

  • Ruth M. Williams

    (University of Oxford)

  • David R. Greaves

    (University of Oxford)

  • Le A. Trinh

    (University of Southern California)

  • Scott E. Fraser

    (University of Southern California)

  • Sarah L. Dallas

    (School of Dentistry, University of Missouri-Kansas City)

  • Robin P. Choudhury

    (University of Oxford)

  • Tatjana Sauka-Spengler

    (University of Oxford)

  • Paul R. Riley

    (University of Oxford
    University of Oxford)

Abstract

Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair.

Suggested Citation

  • Filipa C. Simões & Thomas J. Cahill & Amy Kenyon & Daria Gavriouchkina & Joaquim M. Vieira & Xin Sun & Daniela Pezzolla & Christophe Ravaud & Eva Masmanian & Michael Weinberger & Sarah Mayes & Madelei, 2020. "Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14263-2
    DOI: 10.1038/s41467-019-14263-2
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