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Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury

Abstract

Profibrotic cells that develop upon injury generate permanent scar tissue and impair organ recovery, though their origin and fate are unclear. Here we show that transient expression of ADAM12 (a disintegrin and metalloprotease 12) identifies a distinct proinflammatory subset of platelet-derived growth factor receptor-α–positive stromal cells that are activated upon acute injury in the muscle and dermis. By inducible genetic fate mapping, we demonstrate in vivo that injury-induced ADAM12+ cells are specific progenitors of a major fraction of collagen-overproducing cells generated during scarring, which are progressively eliminated during healing. Genetic ablation of ADAM12+ cells, or knockdown of ADAM12, is sufficient to limit generation of profibrotic cells and interstitial collagen accumulation. ADAM12+ cells induced upon injury are developmentally distinct from muscle and skin lineage cells and are derived from fetal ADAM12+ cells programmed during vascular wall development. Thus, our data identify injury-activated profibrotic progenitors residing in the perivascular space that can be targeted through ADAM12 to limit tissue scarring.

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Figure 1: ADAM12 expression identifies a proinflammatory subset of gp38+PDGFR-α+ stromal cells transiently induced upon dermis and muscle injury.
Figure 2: The majority of myofibroblasts developing in vivo upon injury are progeny of ADAM12+ cells.
Figure 3: ADAM12+ profibrotic progenitors are induced de novo by tissue injury.
Figure 4: Ablation of ADAM12+ cells induced de novo by injury reduces inflammation and tissue fibrosis.
Figure 5: Tissue injury reactivates ADAM12+ cells programmed during nerve and vascular wall development.
Figure 6: Mesenchymal perivascular ADAM12+ cells are profibrotic progenitors.

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Acknowledgements

This work was funded by the Institut Pasteur, grants from the Mairie de Paris, the Agence Nationale de la Recherche and an Excellence grant from the European Commission. S.E.D.C. is funded by La Ligue contre le Cancer. We thank H.-J. Fehling (University Clinics Ulm, Ulm, Germany) for providing the Rosa26floxSTOP-RFP mice, H. Bujard (ZMBH, Heidelberg, Germany) for providing the LC-1 mice and A. Farr (University of Washington, Seattle) for gp38-specific antibody. We thank L. Polomack and the team of the Centre d'Ingénierie Génétique Murine for technical assistance and members of the Development of Lymphoid Tissue Unit for discussions.

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S.D. and S.E.D.C. carried out experiments and analyzed data. F.L. carried out BAC-mice transgenesis. G.E. participated in experiment design and data analysis, and wrote the manuscript. L.P. designed and directed the project, carried out experiments, analyzed data and wrote the manuscript.

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Correspondence to Lucie Peduto.

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Dulauroy, S., Di Carlo, S., Langa, F. et al. Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med 18, 1262–1270 (2012). https://doi.org/10.1038/nm.2848

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