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.

Centre for Inflammation Research University of Edinburgh Edinburgh United Kingdom

Department of Abdominal Surgery University Hospitals Leuven Leuven Belgium

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Biomedical Sciences Humanitas University Milan Italy

Department of Gastroenterology and Hepatology University Hospitals Leuven Leuven Belgium

Department of Gastroenterology Hepatology Leiden University Medical Center Leiden Netherlands

Department of Immunology and Respiratory Research Boehringer Ingelheim Pharmaceuticals Inc Ridgefield Connecticut USA

Department of Microbiology Immunology and Transplantation KU Leuven Leuven Belgium

Department of Pharmaceutical Sciences University of Antwerp Antwerp Belgium

Gastroenterology Research Unit Department of Experimental and Clinical Biomedical Sciences University of Florence Florence Italy

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

Laboratory of Pathology University Hospitals Leuven Leuven Belgium

Laboratory of Translational Cell and Tissue Research Department of Imaging and Pathology KU Leuven Leuven Belgium

Leuven Institute for Single Cell Omics KU Leuven Leuven Belgium

Translational Research Center for Gastrointestinal Disorders Department of Chronic Diseases and Metabolism KU Leuven Leuven Belgium

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