ADAMTS12 promotes fibrosis by restructuring extracellular matrix to enable activation of injury-responsive fibroblasts
Konrad Hoeft, … , Sikander Hayat, Rafael Kramann
Konrad Hoeft, … , Sikander Hayat, Rafael Kramann
Published September 17, 2024
Citation Information: J Clin Invest. 2024;134(18):e170246. https://doi.org/10.1172/JCI170246.
View: Text | PDF
Research Article Cardiology Nephrology Article has an altmetric score of 42

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

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.

Authors

Konrad Hoeft, Lars Koch, Susanne Ziegler, Ling Zhang, Steffen Luetke, Maria C. Tanzer, Debashish Mohanta, David Schumacher, Felix Schreibing, Qingqing Long, Hyojin Kim, Barbara M. Klinkhammer, Carla Schikarski, Sidrah Maryam, Mathijs Baens, Juliane Hermann, Sarah Krieg, Fabian Peisker, Laura De Laporte, Gideon J.L. Schaefer, Sylvia Menzel, Joachim Jankowski, Benjamin D. Humphreys, Adam Wahida, Rebekka K. Schneider, Matthias Versele, Peter Boor, Matthias Mann, Gerhard Sengle, Sikander Hayat, Rafael Kramann

×

Figure 5

CRISPR/Cas9 KO of ADAMTS12 in human PDGFRβ+ cells.

Options: View larger image (or click on image) Download as PowerPoint
CRISPR/Cas9 KO of ADAMTS12 in human PDGFRβ+ cells. (A) COL1A1 RT-qPCR (P...
(A) COL1A1 RT-qPCR (PNTG TGF-β vs. ADAMTS12-KO TGF-β = 0.003) in human PDGFRβ+ kidney cells with either CRISPR/Cas9-induced ADAMTS12-KO or NTG RNA transduction after treatment with TGF-β or vehicle (n = 4 per group). Results were reproduced in 3 independent experiments. (B) Volcano plot of DEGs in WT versus ADAMTS12-KO PDGFRβ+ cells (n = 4 per group). (C) PROGENy pathway analysis of the DEGs shown in B. (D) Top enriched biological process GO terms based on the top downregulated genes in ADAMTS12-KO cells shown in B. (For abbreviations, see Supplemental Table 10.) (E) Trajectory maps of the migration of WT and ADAMTS12-KO PDGFRβ+ cells after treatment with vehicle or TGF-β. Quantification of the average speed per field of view (PNTG TGF-β vs. ADAMTS12-KO TGF-β = 0.0016). Results were reproduced in 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA with Tukey’s post hoc test.