Celiac Disease Histopathology Recapitulates Hedgehog Downregulation, Consistent with Wound Healing Processes Activation
| Autor: | Maria Fiorentino, Gregory Y. Lauwers, Giuseppe Mazzarella, Anna Sapone, Alessio Fasano, Stefania Senger |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Pathology animal structures celiac Cellular differentiation lcsh:Medicine Down-Regulation Bone Morphogenetic Protein 4 Biology Mice 03 medical and health sciences 0302 clinical medicine Intestinal mucosa Downregulation and upregulation Intestine Small medicine Animals Humans Regeneration Hedgehog Proteins Intestinal Mucosa lcsh:Science Wnt Signaling Pathway Hedgehog Cell Proliferation 030304 developmental biology Wound Healing 0303 health sciences Multidisciplinary Stem Cells lcsh:R Wnt signaling pathway Cell Differentiation Epithelial Cells Intestinal epithelium Hedgehog signaling pathway 3. Good health Celiac Disease tem cells Case-Control Studies Bone Morphogenetic Proteins embryonic structures Cytokines Intercellular Signaling Peptides and Proteins lcsh:Q 030211 gastroenterology & hepatology Histopathology Research Article |
| Zdroj: | PLoS ONE PloS one 10 (2015): 1–15. doi:10.1371/journal.pone.0144634 info:cnr-pdr/source/autori:Senger, Stefania; Sapone, Anna; Sapone, Anna; Fiorentino, Maria Rosaria; Mazzarella, Giuseppe; Lauwers, Gregory Y.; Fasano, Alessio/titolo:Celiac disease histopathology recapitulates hedgehog downregulation, consistent with wound healing processes activation/doi:10.1371%2Fjournal.pone.0144634/rivista:PloS one/anno:2015/pagina_da:1/pagina_a:15/intervallo_pagine:1–15/volume:10 PLoS ONE, Vol 10, Iss 12, p e0144634 (2015) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0144634 |
| Popis: | BACKGROUND: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. METHODS AND FINDINGS: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. CONCLUSIONS: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. |
| Databáze: | OpenAIRE |
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