Intercellular interaction between FAP+ fibroblasts and CD150+ inflammatory monocytes mediates fibrostenosis in Crohn’s disease
Journal of Clinical Investigation, vol. 134
Abstract
Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibrostenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate the mechanisms underlying fibrostenosis in CD, we analyzed the transcriptome of cells isolated from the transmural ileum of patients with CD, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from patients without CD. Our computational analysis revealed that profibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibrostenosis in CD.
Authors 28
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Affiliation as printed
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Affiliation as printed
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Centre for Inflammation Research · University of Edinburgh · KU Leuven
Affiliation as printed
Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Affiliation as printed
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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University of Florence · KU Leuven
Affiliation as printed
Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Affiliation as printed
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Affiliation as printed
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Affiliation as printed
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Affiliation as printed
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Affiliation as printed
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Masaryk University · International Clinical Research Center, St. Anne's University Hospital Brno
Affiliation as printed
Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czech Republic
International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
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Affiliation as printed
Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
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Affiliation as printed
Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
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Affiliation as printed
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Boehringer Ingelheim (United States)
Affiliation as printed
Department of Immunology and Respiratory Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Abdominal Surgery, University Hospitals Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Abdominal Surgery, University Hospitals Leuven, Leuven, Belgium
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Masaryk University · Institute of Haematology and Blood Transfusion · International Clinical Research Center, St. Anne's University Hospital Brno
Affiliation as printed
Institute of Hematology and Blood Transfusion, Prague, Czech Republic
International Clinical Research Center, Faculty of Medicine, Masaryk University, Brno, Czech Republic
International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czech Republic
International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
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Affiliation as printed
Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Abdominal Surgery, University Hospitals Leuven, Leuven, Belgium
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Affiliation as printed
Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
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Affiliation as printed
Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
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Affiliation as printed
Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Lukas J.A.C. Hawinkels Aachen Department of Gastroenterology-Hepatology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, Netherlands
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Laboratory of Pathology, University Hospitals Leuven, Leuven, Belgium
Laboratory of Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
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Severine A.R.A. Vermeire corresponding
Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Gianluca Matteoli corresponding
Affiliation as printed
Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium
Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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