Sfrp1 inhibits lung fibroblast invasion during transition to injury induced myofibroblasts.

Autor:	Mayr CH; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Sengupta A; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Asgharpour S; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Ansari M; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.; Institute of Computational Biology, Helmholtz Munich, Munich, Germany., Pestoni JC; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Ogar P; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Angelidis I; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Liontos A; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.; SciLifeLab, Stockholm, Sweden., Rodriguez-Castillo JA; Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany, member of the German Center for Lung Research (DZL)., Lang NJ; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Strunz M; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Porras-Gonzalez D; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Gerckens M; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.; Department of Internal Medicine V, Ludwig-Maximilians University (LMU) Munich, Member of the German Center for Lung Research (DZL), CPC-M bioArchive, Munich, Germany., De Sadeleer LJ; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETA, KU Leuven, Leuven, Belgium., Oehrle B; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Viteri-Alvarez V; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Fernandez IE; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Tallquist M; Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, USA., Irmler M; Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Beckers J; Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.; Chair of Experimental Genetics, Technical University of Munich, Freising, Germany., Eickelberg O; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Stoleriu GM; Department of Internal Medicine V, Ludwig-Maximilians University (LMU) Munich, Member of the German Center for Lung Research (DZL), CPC-M bioArchive, Munich, Germany., Behr J; Department of Internal Medicine V, Ludwig-Maximilians University (LMU) Munich, Member of the German Center for Lung Research (DZL), CPC-M bioArchive, Munich, Germany., Kneidinger N; Department of Internal Medicine V, Ludwig-Maximilians University (LMU) Munich, Member of the German Center for Lung Research (DZL), CPC-M bioArchive, Munich, Germany., Wuyts WA; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETA, KU Leuven, Leuven, Belgium., Wasnick RM; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany., Yildirim AÖ; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.; Institute of Experimental Pneumology, LMU University Hospital, Ludwig-Maximilians University, Munich, Germany., Ahlbrecht K; Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany, member of the German Center for Lung Research (DZL)., Morty RE; Department of Translational Pulmonology, University Hospital Heidelberg, and Translational Lung Research Center (TLRC), member of the German Center for Lung Research (DZL), Heidelberg, Germany., Samakovlis C; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.; SciLifeLab, Stockholm, Sweden., Theis FJ; Institute of Computational Biology, Helmholtz Munich, Munich, Germany.; Department of Mathematics, Technische Universität München, Munich, Germany., Burgstaller G; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.; These authors contributed equally., Schiller HB; Comprehensive Pneumology Center (CPC) / Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany herbert.schiller@helmholtz-muenchen.de gerald.burgstaller@helmholtz-muenchen.de.; Institute of Experimental Pneumology, LMU University Hospital, Ludwig-Maximilians University, Munich, Germany.; These authors contributed equally.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2024 Jan 11. Date of Electronic Publication: 2024 Jan 11.
DOI:	10.1183/13993003.01326-2023
Abstrakt:	Background: Fibroblast to myofibroblast conversion is a major driver of tissue remodeling in organ fibrosis. Distinct lineages of fibroblasts support homeostatic tissue niche functions, yet, their specific activation states and phenotypic trajectories during injury and repair have remained unclear. Methods: We combined spatial transcriptomics, multiplexed immunostainings, longitudinal single-cell RNA-seq and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. Our findings were validated in IPF patient tissues in situ as well as in cell differentiation and invasion assays using patient lung fibroblasts. Cell differentiation and invasion assays established a function of SFRP1 in regulating human lung fibroblast invasion in response to TGFβ1. Measurements and Main Results: We discovered a transitional fibroblast state characterized by high Sfrp1 expression, derived from both Tcf21 -Cre lineage positive and negative cells. Sfrp1 + cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1 + transitional fibroblasts and Cthrc1 + myofibroblasts. TGFβ1 downregulated SFRP1 in non-invasive transitional cells and induced their switch to an invasive CTHRC1+ myofibroblast identity. Finally, using loss of function studies we showed that SFRP1 modulates TGFβ1 induced fibroblast invasion and RHOA pathway activity. Conclusions: Our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies SFRP1 as a modulator of TGFβ1 driven fibroblast phenotypes in fibrogenesis. These findings are relevant in the context of therapeutic interventions that aim at limiting or reversing fibroblast foci formation. (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)
Databáze:	MEDLINE
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