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.
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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

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Figure 3

Visium spatial transcriptomics of WT and Adamts12–/– mice after MI.

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Visium spatial transcriptomics of WT and Adamts12–/– mice after MI. (A) ...
(A) Experimental design of MI surgeries for Visium spatial transcriptomics. The schematic drawing was created with BioRender (BioRender.com). (B) LV-EF of WT and Adamts12–/– mice 7 days after MI (n = 4 per group). *P < 0.05 (P = 0.037), by unpaired t test. Selected mice for spatial transcriptomics are marked by arrows. (C) Spatial niches in spatial transcriptomic data of WT and Adamts12–/– mice (n = 2 per group). (D) Spatial expression of Adamts12 in WT mice. norm. exp., normalized expression. (E) Total Adamts12 expression stratified by zone and cell type. (F) Bar plot of Tangram prediction scores in IZs of WT versus Adamts12–/– mice after normalization via log2 transformation. (G) DEGs in WT versus Adamts12–/– mice in IZ. (H) Top enriched Reactome pathways in IZs of Adamts12—/— mice based on the DEGs shown in G. Str Muscle Contraction, striated muscle contraction. (I) PROGENy pathway analysis based on the DEGs shown in G. (J) Fibroblast subset prediction scores adjusted for the initially imputed Tangram fibroblast prediction score. Spots show the fibroblast subtype with the highest prediction score. Fib, fibroblast; Ifn Fib, interferon fibroblasts; IR Fib, Atf3+ injury-responsive fibroblasts. (K) Tangram-adjusted fibroblast subset prediction scores stratified by zone. (L) Tangram-adjusted fibroblast subset prediction scores within the IZ stratified by genotype. ****P < 0.0001, by unpaired t test. (M) Spatial FeaturePlot of fibroblast 3 (Fib 3) Tangram-adjusted prediction (T.-adj.) scores in WT sample 1 and Adamts12–/– sample 1. (N) Spatial FeaturePlot of IR fibroblast (IR Fib) Tangram-adjusted prediction scores in WT sample 1 and Adamts12–/– sample 1.