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

• Published in: The Journal of clinical investigation Vol. 134; no. 18
• Main Authors: Hoeft, Konrad, Koch, Lars, Ziegler, Susanne, Zhang, Ling, Luetke, Steffen, Tanzer, Maria C, Mohanta, Debashish, Schumacher, David, Schreibing, Felix, Long, Qingqing, Kim, Hyojin, Klinkhammer, Barbara M, Schikarski, Carla, Maryam, Sidrah, Baens, Mathijs, Hermann, Juliane, Krieg, Sarah, Peisker, Fabian, De Laporte, Laura, Schaefer, Gideon Jl, Menzel, Sylvia, Jankowski, Joachim, Humphreys, Benjamin D, Wahida, Adam, Schneider, Rebekka K, Versele, Matthias, Boor, Peter, Mann, Matthias, Sengle, Gerhard, Hayat, Sikander, Kramann, Rafael
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.09.2024
• Subjects: ADAMTS Proteins - genetics; ADAMTS Proteins - metabolism; Animals; Extracellular matrix; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Health aspects; Humans; Medical research; Medicine, Experimental; Mice; Mice, Knockout; Myofibroblasts - metabolism; Myofibroblasts - pathology; Physiological aspects; Proteases; Reorganization and restructuring; RNA sequencing; Scientific equipment and supplies industry; Signal Transduction; Wounds and injuries; United States; Germany; Iraq; Cardiology; Nephrology; Fibrosis
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI170246

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.