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

Autor: Hoeft K; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Koch L; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Ziegler S; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Zhang L; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Luetke S; Department of Pediatrics and Adolescent Medicine.; Center for Biochemistry, Medical Faculty, and.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Cologne Center for Musculoskeletal Biomechanics (CCMB), Cologne, Germany., Tanzer MC; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.; Max-Planck Institute of Biochemistry, Martinsried, Germany., Mohanta D; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Schumacher D; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany.; Department of Anesthesiology, RWTH Aachen University, Aachen, Germany., Schreibing F; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany.; Sequantrix GmbH, Aachen, Germany., Long Q; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Kim H; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Klinkhammer BM; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Schikarski C; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Maryam S; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Baens M; CISTIM Leuven vzw, Leuven, Belgium., Hermann J; Institute for Molecular Cardiovascular Research, RWTH Aachen University, Medical Faculty, Aachen, Germany., Krieg S; Institute of Biochemistry and Molecular Biology, and., Peisker F; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., De Laporte L; Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Aachen, Germany.; Institute of Applied Medical Engineering, Department of Advanced Materials for Medicine, University Hospital RWTH Aachen, Aachen, Germany.; DWI-Leibniz Institute of Interactive Materials, Aachen, Germany., Schaefer GJ; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Menzel S; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Jankowski J; Institute for Molecular Cardiovascular Research, RWTH Aachen University, Medical Faculty, Aachen, Germany., Humphreys BD; Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA., Wahida A; Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany., Schneider RK; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.; Department of Cell Biology, Institute for Biomedical Technologies, RWTH Aachen University, Aachen, Germany., Versele M; CISTIM Leuven vzw, Leuven, Belgium., Boor P; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany.; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Mann M; Max-Planck Institute of Biochemistry, Martinsried, Germany., Sengle G; Department of Pediatrics and Adolescent Medicine.; Center for Biochemistry, Medical Faculty, and.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.; Cologne Center for Musculoskeletal Biomechanics (CCMB), Cologne, Germany., Hayat S; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany., Kramann R; Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), RWTH Aachen University, Medical Faculty, Aachen, Germany.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2024 Sep 17; Vol. 134 (18). Date of Electronic Publication: 2024 Sep 17.
DOI: 10.1172/JCI170246
Abstrakt: 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.
Databáze: MEDLINE