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ADAMTS12 serves as a checkpoint in fibrosis that controls migration and expansion 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-sequencing (scRNA-seq) technologies have helped elucidate fibroblast heterogeneity and ontogeny beyond fibroblast to myofibroblast differentiation, the novel identified fibroblast populations remain ill-defined, both in respect to the molecular cues driving their differentiation, and their subsequent role in fibrosis. Here we identify the metalloprotease ADAMTS12 in an unbiased manner as a fibroblast-specific gene that is strongly upregulated during fibrogenesis in mice and humans. In vivo knockout studies in mice confirmed that Adamts12 is critical during fibrogenesis in heart and kidney. Leveraging spatial transcriptomics, CRISPR-Cas9 gene editing and expression of catalytically active or inactive ADAMTS12 we demonstrate that the protease domain of Adamts12 controls fibrogenesis by licensing expansion and migration of a distinct fibroblast subset defined by Mt1 gene expression and strong JAK-STAT signaling.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Mario Oroshi

LAB HEAD: Univ.-Prof. Dr. med. Rafael Kramann

PROVIDER: PXD040152 | Pride | 2024-07-01

REPOSITORIES: Pride

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			Action	DRS
	20211022_EXPL0_MaTa_SA_fibroblasts_ADAMTS12ko_1.raw	Raw
	20211022_EXPL0_MaTa_SA_fibroblasts_ADAMTS12ko_2.raw	Raw
	20211022_EXPL0_MaTa_SA_fibroblasts_ADAMTS12ko_3.raw	Raw
	20211022_EXPL0_MaTa_SA_fibroblasts_NT_1.raw	Raw
	20211022_EXPL0_MaTa_SA_fibroblasts_NT_2.raw	Raw

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