Document Detail


Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development.
MedLine Citation:
PMID:  20542037     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Intestinal stem cells (ISCs) are regulated by the mesenchymal environment via physical interaction and diffusible factors. We examined the role of Indian hedgehog (Ihh) in mesenchymal organization and the mechanisms by which perturbations in epithelial-mesenchymal interactions affect ISC fate.
METHODS: We generated mice with intestinal epithelial-specific disruption of Ihh. Gross and microscopic anatomical changes were determined using histologic, immunohistochemical, and in situ hybridization analyses. Molecular mechanisms were elucidated by expression profiling and in vitro analyses.
RESULTS: Deletion of intestinal epithelial Ihh disrupted the intestinal mesenchymal architecture, demonstrated by loss of the muscularis mucosae, deterioration of the extracellular matrix, and reductions in numbers of crypt myofibroblasts. Concurrently, the epithelial compartment had increased Wnt signaling, disturbed crypt polarity and architecture, defective enterocyte differentiation, and increased and ectopic proliferation that was accompanied by increased numbers of ISCs. Mechanistic studies revealed that Hh inhibition deregulates bone morphogenetic protein signaling, increases matrix metalloproteinase levels, and disrupts extracellular matrix proteins, fostering a proliferative environment for ISCs and progenitor cells.
CONCLUSIONS: Ihh regulates ISC self-renewal and differentiation. Intestinal epithelial Ihh signals to the mesenchymal compartment to regulate formation and proliferation of mesenchymal cells, which in turn affect epithelial proliferation and differentiation. These findings provide a basis for analyses of the role of the muscularis mucosae in ISC regulation.
Authors:
Cynthia Kosinski; Daniel E Stange; Chuanrui Xu; Annie Sy Chan; Coral Ho; Siu Tsan Yuen; Randy C Mifflin; Don W Powell; Hans Clevers; Suet Yi Leung; Xin Chen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-06-11
Journal Detail:
Title:  Gastroenterology     Volume:  139     ISSN:  1528-0012     ISO Abbreviation:  Gastroenterology     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-30     Completed Date:  2010-09-20     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  893-903     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE18393
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MeSH Terms
Descriptor/Qualifier:
Animals
Basement Membrane / metabolism
Cell Communication*
Cell Differentiation
Cell Lineage
Cell Proliferation
Colitis / metabolism,  pathology
Colon / metabolism*,  pathology
Epithelial Cells / metabolism*,  pathology
Extracellular Matrix Proteins / genetics
Gene Expression Profiling
Gene Expression Regulation
Genotype
Hedgehog Proteins / deficiency,  genetics,  metabolism*
Immunohistochemistry
In Situ Hybridization
Integrases / genetics
Intestinal Mucosa / metabolism*,  pathology
Mesoderm / metabolism*,  pathology
Mice
Mice, Knockout
Microfilament Proteins / genetics
Paracrine Communication
Phenotype
Signal Transduction*
Stem Cells / metabolism*,  pathology
Wnt Proteins / metabolism
beta Catenin / metabolism
Grant Support
ID/Acronym/Agency:
R01 CA136606/CA/NCI NIH HHS; R01 CA136606-01A2/CA/NCI NIH HHS; R01CA127229/CA/NCI NIH HHS; R01CA136606/CA/NCI NIH HHS; R01DK55783/DK/NIDDK NIH HHS; R21 DK069309/DK/NIDDK NIH HHS; R21 DK069309-01A1/DK/NIDDK NIH HHS; R21DK069309/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Catnb protein, mouse; 0/Extracellular Matrix Proteins; 0/Hedgehog Proteins; 0/Microfilament Proteins; 0/Wnt Proteins; 0/beta Catenin; 0/ihh protein, mouse; 0/villin; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases
Comments/Corrections

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