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Hoeft, K.* ; Koch, L.* ; Ziegler, S.* ; Zhang, L.* ; Luetke, S.* ; Tanzer, M.C.* ; Mohanta, D.* ; Schumacher, D.* ; Schreibing, F.* ; Long, Q.* ; Kim, H.* ; Klinkhammer, B.M.* ; Schikarski, C.* ; Maryam, S.* ; Baens, M.* ; Hermann, J.* ; Krieg, S.* ; Peisker, F.* ; De Laporte, L.* ; Schaefer, G.J.L.* ; Menzel, S.* ; Jankowski, J.* ; Humphreys, B.D.* ; Wahida, A. ; Schneider, R.K.* ; Versele, M.* ; Boor, P.* ; Mann, M.* ; Sengle, G.* ; Hayat, S.* ; Kramann, R.*

ADAMTS12 promotes fibrosis by restructuring extracellular matrix to enable activation of injury-responsive fibroblasts.

J. Clin. Invest. 134:e170246 (2024)
Postprint DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Fibrosis represents the uncontrolled replacement of parenchymal tissue with extracellular matrix (ECM) produced by myofibroblasts. While genetic fate-tracing and single-cell RNA-Seq technologies have helped elucidate fibroblast heterogeneity and ontogeny beyond fibroblast to myofibroblast differentiation, newly identified fibroblast populations remain ill defined, with respect to both the molecular cues driving their differentiation and their subsequent role in fibrosis. Using an unbiased approach, we identified the metalloprotease ADAMTS12 as a fibroblast-specific gene that is strongly upregulated during active fibrogenesis in humans and mice. Functional in vivo KO studies in mice confirmed that Adamts12 was critical during fibrogenesis in both heart and kidney. Mechanistically, using a combination of spatial transcriptomics and expression of catalytically active or inactive ADAMTS12, we demonstrated that the active protease of ADAMTS12 shaped ECM composition and cleaved hemicentin 1 (HMCN1) to enable the activation and migration of a distinct injury-responsive fibroblast subset defined by aberrant high JAK/STAT signaling.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cardiology ; Fibrosis ; Nephrology; Pathway Activation; Cells; Contributes; Growth; Image
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 134, Heft: 18, Seiten: , Artikelnummer: e170246 Supplement: ,
Verlag American Society of Clinical Investigation
Verlagsort 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Förderungen Max Planck Society for the Advancement of Science
German Society for Cardiology Otto-Hess MD
German Research Foundation (DFG)
Europe-an Research Council
Else Kroener Fresenius Foundation (EKFS)
BMBF
BMBF consortia CureFib
DFG
European Research Council
Federal Ministry of Education and Research (BMBF)
German Society of Internal Medicine Peter Scriba