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dc.contributor.authorSenger, Stefaniaen_US
dc.contributor.authorSapone, Annaen_US
dc.contributor.authorFiorentino, Maria Rosariaen_US
dc.contributor.authorMazzarella, Giuseppeen_US
dc.contributor.authorLauwers, Gregory Y.en_US
dc.contributor.authorFasano, Alessioen_US
dc.date.accessioned2016-01-04T19:23:47Z
dc.date.issued2015en_US
dc.identifier.citationSenger, Stefania, Anna Sapone, Maria Rosaria Fiorentino, Giuseppe Mazzarella, Gregory Y. Lauwers, and Alessio Fasano. 2015. “Celiac Disease Histopathology Recapitulates Hedgehog Downregulation, Consistent with Wound Healing Processes Activation.” PLoS ONE 10 (12): e0144634. doi:10.1371/journal.pone.0144634. http://dx.doi.org/10.1371/journal.pone.0144634.en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:23993597
dc.description.abstractBackground: 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.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pone.0144634en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674131/pdf/en
dash.licenseLAAen_US
dc.titleCeliac Disease Histopathology Recapitulates Hedgehog Downregulation, Consistent with Wound Healing Processes Activationen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS ONEen
dash.depositing.authorSenger, Stefaniaen_US
dc.date.available2016-01-04T19:23:47Z
dc.identifier.doi10.1371/journal.pone.0144634*
dash.contributor.affiliatedSapone, Anna
dash.contributor.affiliatedFiorentino, Maria
dash.contributor.affiliatedFasano, Alessio
dash.contributor.affiliatedSenger, Stefania
dash.contributor.affiliatedLauwers, Gregory Y.


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