TY - JOUR
T1 - Phagocytosis of Wnt inhibitor SFRP4 by late wound macrophages drives chronic Wnt activity for fibrotic skin healing
AU - Gay, Denise
AU - Ghinatti, Giulia
AU - Guerrero-Juarez, Christian F.
AU - Ferrer, Rubén A.
AU - Ferri, Federica
AU - Lim, Chae Ho
AU - Murakami, Shohei
AU - Gault, Nathalie
AU - Barroca, Vilma
AU - Rombeau, Isabelle
AU - Mauffrey, Philippe
AU - Irbah, Lamya
AU - Treffeisen, Elsa
AU - Franz, Sandra
AU - Boissonnas, Alexandre
AU - Combadière, Christophe
AU - Ito, Mayumi
AU - Plikus, Maksim V.
AU - Romeo, Paul Henri
N1 - Funding Information:
We wish to thank Q. Sun (New York University Langone Medical Center, New York, NY), S. Moreno, and C. Torres for thoughtful suggestions; C. Joubert and V. Durand for assistance with animal protocols (CEA, Fontenay-aux-Roses cedex, France) and A. Muro (ICGEB, Trieste, Italy), D. O'Gorman (University of Western Ontario, London, Canada), and M. M. Marks (University of Pennsylvania, Philadelphia, USA) for providing valuable information about EDA-FN+/− mice and Dupuytren's syndrome and help with experimental design, respectively; S. Aractingi (Hôpital Cochin and Université Paris Descartes, Paris, France) for valuable insight into HS; J. C. Simon, M. Ziemer, S. Grunewald, and J. Thees (Department of Dermatology, University Leipzig Medical Center, Leipzig, Germany) for help in accessing HS tissues; and the NYUMC Genome Technology Center (in particular, A. Heguy, Y. Zhang, and C. Marier) for expert assistance with library preparation, Illumina sequencing and Cell Ranger alignment. D.G. has salary support from INSERM and CEA funding. This work was supported by grants from Inserm, CEA, University Paris-Diderot, and University Paris-Sud. M.V.P. is supported by the NIH NIAMS grants R01-AR067273 and R01-AR069653 and Pew Charitable Trust grant. C.F.G.-J. is supported by the UC Irvine Chancellor's ADVANCE Postdoctoral Fellowship Program, an NSF-Simons Postdoctoral Fellowship, NSF Grant DMS1763272, and Simons Foundation Grant 594598. R.A.F. is supported by a DFG grant FE 1850/1-1. S.F. is supported by the German Research Council DFG SFB-TR67 project B3 and DFG grant FR2671/4-1. M.I. and C.H.L. partial support is through NIH NIAMS R01-AR059768 and R01-AR066022. The NYU Langone Genome Technology Center is partially supported by grant NIH NCI P30CA016087.
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2020
Y1 - 2020
N2 - Human and murine skin wounding commonly results in fibrotic scarring, but the murine wounding model wound-induced hair neogenesis (WIHN) can frequently result in a regenerative repair response. Here, we show in single-cell RNA sequencing comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.
AB - Human and murine skin wounding commonly results in fibrotic scarring, but the murine wounding model wound-induced hair neogenesis (WIHN) can frequently result in a regenerative repair response. Here, we show in single-cell RNA sequencing comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.
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U2 - 10.1126/sciadv.aay3704
DO - 10.1126/sciadv.aay3704
M3 - Article
C2 - 32219160
AN - SCOPUS:85082175922
SN - 2375-2548
VL - 6
JO - Science advances
JF - Science advances
IS - 12
M1 - eaay3704
ER -