TY - JOUR
T1 - ADAMTS12 promotes fibrosis by restructuring extracellular matrix to enable activation of injury-responsive fibroblasts
AU - Hoeft, Konrad
AU - Koch, Lars
AU - Ziegler, Susanne
AU - Zhang, Ling
AU - Luetke, Steffen
AU - Tanzer, Maria C.
AU - Mohanta, Debashish
AU - Schumacher, David
AU - Schreibing, Felix
AU - Long, Qingqing
AU - Kim, Hyojin
AU - Klinkhammer, Barbara M.
AU - Schikarski, Carla
AU - Maryam, Sidrah
AU - Baens, Mathijs
AU - Hermann, Juliane
AU - Krieg, Sarah
AU - Peisker, Fabian
AU - De Laporte, Laura
AU - Schaefer, Gideon J.L.
AU - Menzel, Sylvia
AU - Jankowski, Joachim
AU - Humphreys, Benjamin D.
AU - Wahida, Adam
AU - Schneider, Rebekka K.
AU - Versele, Matthias
AU - Boor, Peter
AU - Mann, Matthias
AU - Sengle, Gerhard
AU - Hayat, Sikander
AU - Kramann, Rafael
N1 - Publisher Copyright:
© 2024, Hoeft et al.
PY - 2024/9/17
Y1 - 2024/9/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85204418826&partnerID=8YFLogxK
U2 - 10.1172/JCI170246
DO - 10.1172/JCI170246
M3 - Article
C2 - 39286973
AN - SCOPUS:85204418826
SN - 0021-9738
VL - 134
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 18
M1 - e170246
ER -