Fibroblast Activation Protein Expression Differs Between Inflamed and Fibrostenotic Inflammatory Bowel Disease
JCC Plus, vol. 1
Abstract
ABSTRACT Background Intestinal fibrosis is a well‐known complication of inflammatory bowel disease (IBD). The development of anti‐fibrotic agents is hampered by limited validated outcome measures. Fibroblast activation protein (FAP) has been proposed as a fibrosis marker in immune‐mediated inflammatory diseases, including IBD. Our aim was to assess FAP expression in both Crohn's disease (CD) and therapy‐refractory ulcerative colitis (UC) and to characterise its spatial and cellular distribution. Methods We combined qPCR, immunohistochemistry (IHC), and imaging mass cytometry (IMC) to investigate FAP expression in transmural resection specimens from CD and UC patients and non‐IBD controls. Fibrosis and inflammation were evaluated and scored using H&E and Masson's trichrome staining. Primary intestinal fibroblasts were cultured for 3 weeks to allow matrix deposition, after which FAP was visualised using immunofluorescence staining. Results FAP mRNA and total FAP protein levels were increased in inflamed and fibrostenotic CD and therapy‐refractory UC and were mainly found in the submucosa and serosa. IMC revealed that FAP expression was predominantly expressed by CD90 + stromal cells, showing higher cellular FAP levels in inflamed tissues compared to fibrostenotic tissues. This discrepancy between total and cellular FAP in fibrostenotic tissue could potentially be explained by the observations suggesting that fibrostenotic segments showed increased extracellular FAP expression. In vitro experiments supported the finding of extracellular FAP in matrix deposited by primary intestinal fibroblasts. Conclusions FAP is strongly expressed in inflamed and fibrostenotic CD and, albeit to a lesser extent, in therapy‐refractory UC, with total FAP levels being highest in fibrostenotic disease. Cellular FAP expression is predominantly confined to CD90 + stromal cells in inflamed tissues, whereas fibrostenotic lesions are characterised by increased extracellular FAP.
Authors 15
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Amsterdam University Medical Centers · Cancer Center Amsterdam · Amsterdam Gastroenterology Endocrinology Metabolism · University of Amsterdam
Affiliation as printed
Amsterdam Gastroenterology Endocrinology Metabolism Amsterdam the Netherlands
Department of Gastroenterology & Hepatology Amsterdam University Medical Centres‐ University of Amsterdam Amsterdam the Netherlands
Laboratory of Experimental Oncology and Radiobiology Cancer Center Amsterdam Amsterdam UMC and University of Amsterdam Amsterdam the Netherlands
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Bram W. van Os Aachen Department of Gastroenterology and Hepatology Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology & Hepatology Leiden University Medical Center Leiden the Netherlands
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Affiliation as printed
Katholieke Universiteit Leuven—Translational Research Center for Gastrointestinal Disorders (TARGID) Leuven Belgium
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Amsterdam University Medical Centers · Cancer Center Amsterdam · University of Amsterdam
Affiliation as printed
Department of Gastroenterology & Hepatology Amsterdam University Medical Centres‐ University of Amsterdam Amsterdam the Netherlands
Laboratory of Experimental Oncology and Radiobiology Cancer Center Amsterdam Amsterdam UMC and University of Amsterdam Amsterdam the Netherlands
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Universitair Ziekenhuis Leuven
Affiliation as printed
Department of Pathology Universitair Ziekenhuis Leuven Leuven Belgium
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Luuk J. A. C. Hawinkels Aachen Department of Gastroenterology and Hepatology Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology & Hepatology Leiden University Medical Center Leiden the Netherlands
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Affiliation as printed
Katholieke Universiteit Leuven—Translational Research Center for Gastrointestinal Disorders (TARGID) Leuven Belgium
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Jie Su Aachen Department of Gastroenterology and Hepatology Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology & Hepatology Leiden University Medical Center Leiden the Netherlands
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Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Surgery Amsterdam University Medical Centres—University of Amsterdam Amsterdam the Netherlands
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Affiliation as printed
Department of Surgery Flevoziekenhuis Almere the Netherlands
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Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Gastroenterology & Hepatology Amsterdam University Medical Centres‐ University of Amsterdam Amsterdam the Netherlands
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Amsterdam University Medical Centers · Cancer Center Amsterdam · University of Amsterdam
Affiliation as printed
Department of Gastroenterology & Hepatology Amsterdam University Medical Centres‐ University of Amsterdam Amsterdam the Netherlands
Laboratory of Experimental Oncology and Radiobiology Cancer Center Amsterdam Amsterdam UMC and University of Amsterdam Amsterdam the Netherlands
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Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Amsterdam University Medical Centres—University of Amsterdam Tytgat Institute for Liver and Intestinal Research Amsterdam the Netherlands
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Marieke C. Barnhoorn Aachen Department of Gastroenterology and Hepatology Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology & Hepatology Leiden University Medical Center Leiden the Netherlands
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Mark Lowenberg corresponding
Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Gastroenterology & Hepatology Amsterdam University Medical Centres‐ University of Amsterdam Amsterdam the Netherlands
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