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

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-09-17 DOI:10.1172/JCI170246
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 Jl 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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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.

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ADAMTS12 通过重组细胞外基质促进纤维化,从而激活对损伤有反应的成纤维细胞。
纤维化是指由肌成纤维细胞产生的细胞外基质(ECM)不受控制地取代实质组织。虽然基因命运追踪和单细胞 RNA-Seq 技术有助于阐明成纤维细胞的异质性和从成纤维细胞到肌成纤维细胞分化的本体,但新发现的成纤维细胞群在驱动其分化的分子线索及其随后在纤维化中的作用方面仍然定义不清。通过无偏见的方法,我们发现金属蛋白酶 ADAMTS12 是成纤维细胞特异性基因,在人类和小鼠活跃的纤维化过程中会强烈上调。在小鼠体内进行的功能性 KO 研究证实,Adamts12 在心脏和肾脏的纤维形成过程中起着关键作用。从机理上讲,利用空间转录组学和具有催化活性或无活性的 ADAMTS12 的表达相结合的方法,我们证明了 ADAMTS12 的活性蛋白酶可改变 ECM 的组成和裂解半缩醛素 1 (HMCN1),从而使由异常的高 JAK/STAT 信号转导所定义的独特的损伤反应性成纤维细胞亚群得以活化和迁移。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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