title: Celiac Disease Histopathology Recapitulates Hedgehog Downregulation, Consistent with Wound Healing Processes Activation.
abstract: In celiac disease (CD), intestinal epithelium damage occurs secondary to an immune insult and is characterized by blunting of the villi and crypt hyperplasia. Similarities between Hedgehog (Hh)/BMP4 downregulation, as reported in a mouse model, and CD histopathology, suggest mechanistic involvement of Hh/BMP4/WNT pathways in proliferation and differentiation of immature epithelial cells in the context of human intestinal homeostasis and regeneration after damage. Herein we examined the nature of intestinal crypt hyperplasia and involvement of Hh/BMP4 in CD histopathology.
  
  
  
  Immunohistochemistry, qPCR and in situ hybridization were used to study a cohort of 24 healthy controls (HC) and 24 patients with diagnosed acute celiac disease (A-CD) intestinal biopsies. In A-CD we observed an increase in cells positive for Leucin-rich repeat-containing G protein-coupled receptor 5 (LGR5), an epithelial stem cell specific marker and expansion of WNT responding compartment. Further, we observed alteration in number and distribution of mesenchymal cells, predicted to be part of the intestinal stem cells niche. At the molecular level we found downregulation of indian hedgehog (IHH) and other components of the Hh pathway, but we did not observe a concurrent downregulation of BMP4. However, we observed upregulation of BMPs antagonists, gremlin 1 and gremlin 2.
  
  
  
  Our data suggest that acute CD histopathology partially recapitulates the phenotype reported in Hh knockdown models. Specifically, Hh/BMP4 paradigm appears to be decoupled in CD, as the expansion of the immature cell population does not occur consequent to downregulation of BMP4. Instead, we provide evidence that upregulation of BMP antagonists play a key role in intestinal crypt hyperplasia. This study sheds light on the molecular mechanisms underlying CD histopathology and the limitations in the use of mouse models for celiac disease.
authors.affiliation: Center for Mucosal Immunology and Biology Research, Massachusetts General Hospital for Children and Celiac Program at Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Stefania
authors.initials: S
authors.lastname: Senger
authors.affiliation: Center for Mucosal Immunology and Biology Research, Massachusetts General Hospital for Children and Celiac Program at Harvard Medical School, Charlestown, Massachusetts, United States of America.|Celiac Center, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Sapone
authors.affiliation: Center for Mucosal Immunology and Biology Research, Massachusetts General Hospital for Children and Celiac Program at Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Fiorentino
authors.affiliation: Institute of Food Sciences, National Research Council (CNR), Avellino, 83100, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mazzarella
authors.affiliation: Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, United States of America.
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.affiliation: Center for Mucosal Immunology and Biology Research, Massachusetts General Hospital for Children and Celiac Program at Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Alessio
authors.initials: A
authors.lastname: Fasano
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D016022:Case-Control Studies; D002446:Celiac Disease / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D051379:Mice; D012038:Regeneration / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism; D060449:Wnt Signaling Pathway; D014945:Wound Healing / Q000502:physiology*
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; C486399:GREM1 protein, human; C495107:GREM2 protein, human; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins