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

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

Author(s): Hoeft, K; Koch, L; Ziegler, S; Zhang, L; Luetke, S; Tanzer, MC; Mohanta, D; Schumacher, D; Schreibing, F; Long, Q; Kim, H; Klinkhammer, BM; Schikarski, C; Maryam, S; Baens, M; Hermann, J; Krieg, S; Peisker, F; De Laporte, L; Schaefer, GJ; Menzel, S; Jankowski, J; Humphreys, BD; Wahida, A; Schneider, RK; Versele, M; Boor, P; Mann, M; Sengle, G; Hayat, S; Kramann, R;
Journal Title: Journal of Clinical Investigation
Abstract: 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.
Publisher: ASCI
Keywords: Animals; Mice; *Extracellular Matrix/metabolism/pathology; *Fibrosis; Humans; *Mice, Knockout; Fibroblasts/metabolism/pathology; ADAMTS Proteins/genetics/metabolism; Signal Transduction; Myofibroblasts/metabolism/pathology
Research Division(s): Advanced Technology And Biology
PubMed ID: 39286973
Publisher's Version: https://doi.org/10.1172/JCI170246
Open Access at Publisher's Site: https://doi.org/10.1172/JCI170246
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-04 10:45:00

Last Modified: 2024-10-04 10:51:24