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

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, Madeleine E. Lemieux, Damien N. Barnette, Mala Gunadasa-Rohling, Ruth M. Williams, David R. Greaves, Le A. Trinh, Scott E. Fraser, Sarah L. Dallas, Robin P. Choudhury, Tatjana Sauka-Spengler and Paul R. Riley ()
Additional contact information
Filipa C. Simões: University of Oxford
Thomas J. Cahill: University of Oxford
Amy Kenyon: University of Oxford
Daria Gavriouchkina: University of Oxford
Joaquim M. Vieira: University of Oxford
Xin Sun: University of Oxford
Daniela Pezzolla: University of Oxford
Christophe Ravaud: University of Oxford
Eva Masmanian: University of Oxford
Michael Weinberger: University of Oxford
Sarah Mayes: 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

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14263-2

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