ADAMTS12 promotes fibrosis by restructuring extracellular matrix to enable activation of injury-responsive fibroblasts
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.
Authors
- Lars Koch (ORCID: https://orcid.org/0000-0002-3181-3050)
- Matthias Mann
- Sarah Krieg (ORCID: https://orcid.org/0000-0003-1329-0185)
- Matthias Versele (ORCID: https://orcid.org/0000-0001-9274-6579)
- Gerhard Sengle (ORCID: https://orcid.org/0000-0003-3932-1242)
- Gideon J L Schaefer
- Sylvia Menzel
- Qingqing Long (ORCID: https://orcid.org/0009-0009-3520-0129)
- Rafael Kramann (ORCID: https://orcid.org/0000-0003-4048-6351)
- Juliane Hermann
- Sidrah Maryam
- Mathijs Baens (ORCID: https://orcid.org/0000-0002-8172-5649)
- Sikander Hayat (ORCID: https://orcid.org/0000-0001-5919-8371)
- Benjamin D. Humphreys (ORCID: https://orcid.org/0000-0002-6420-8703)
- Peter Boor (ORCID: https://orcid.org/0000-0001-9921-4284)
- David Schumacher (ORCID: https://orcid.org/0000-0002-2308-6543)
- Maria C. Tanzer (ORCID: https://orcid.org/0000-0002-4657-9869)
- Felix Schreibing (ORCID: https://orcid.org/0000-0003-0275-4386)
- Laura De Laporte (ORCID: https://orcid.org/0000-0002-9438-0977)
- Barbara M. Klinkhammer (ORCID: https://orcid.org/0000-0002-1566-7129)
- Susanne Ziegler (ORCID: https://orcid.org/0000-0002-4824-2776)
- Rebekka K. Schneider (ORCID: https://orcid.org/0000-0002-0749-1565)
- Fabian Peisker (ORCID: https://orcid.org/0000-0003-0123-8179)
- Adam Wahida (ORCID: https://orcid.org/0000-0002-8856-8834)
- Joachim Jankowski (ORCID: https://orcid.org/0000-0002-4528-2967)
- Konrad Hoeft (ORCID: https://orcid.org/0000-0002-0265-0061)
- Hyojin Kim (ORCID: https://orcid.org/0000-0003-1553-4702)
- Steffen Luetke
- Carla Sophie Schikarski
- Debashish Mohanta
- Ling Zhang (ORCID: https://orcid.org/0000-0001-5850-6811)
Institutions
- Citrix (Switzerland) (CH)
- The University of Melbourne (AU)
- University of Cologne (DE)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Washington University in St. Louis (US)
- Helmholtz Zentrum München (DE)
- DWI – Leibniz Institute for Interactive Materials (DE)
- Erasmus MC Cancer Institute (NL)
- Max Planck Institute of Biochemistry (DE)
- RWTH Aachen University (DE)
- KU Leuven (BE)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1172/jci170246
- Citations
- 16
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 6.43
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- RWTH Aachen University
- Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen
- European Research Council
- Medizinische Fakultät, RWTH Aachen University