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Article: Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development

TitleIndian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development
Authors
KeywordsBMP
ECM
Hedgehog Signaling
MMP
Issue Date2010
PublisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
Citation
Gastroenterology, 2010, v. 139 n. 3, p. 893-903 How to Cite?
AbstractBackground & 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. © 2010 by the AGA Institute.
Persistent Identifierhttp://hdl.handle.net/10722/123825
ISSN
2015 Impact Factor: 18.187
2015 SCImago Journal Rankings: 7.170
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of HealthR21DK069309
R01CA136606
R01CA127229
R01DK55783
Research Grants Council of the Hong Kong Special Administrative RegionHKU7524/06M
The University of Hong Kong
California Institute for Regenerative Medicine
Deutsche Forschungsgemeinschaft (DFG)Sta1065/1-1
Funding Information:

This work is supported in part by National Institutes of Health grants R21DK069309 and R01CA136606 to X.C.; R01CA127229 and R01DK55783 to D.W.P.; a grant from the Research Grants Council of the Hong Kong Special Administrative Region (Project No. HKU7524/06M) to S.Y.L. and X.C.; a grant from Strategic Research Theme on Cancer from The University of Hong Kong to S.Y.L. C.K. is supported by a stem cell fellowship provided by the California Institute for Regenerative Medicine; and D.E.S. is supported by Deutsche Forschungsgemeinschaft (DFG, Sta1065/1-1). The funding agencies have no role in data collection, analysis, and interpretation.

References

 

DC FieldValueLanguage
dc.contributor.authorKosinski, Cen_HK
dc.contributor.authorStange, DEen_HK
dc.contributor.authorXu, Cen_HK
dc.contributor.authorChan, ASen_HK
dc.contributor.authorHo, Cen_HK
dc.contributor.authorYuen, STen_HK
dc.contributor.authorMifflin, RCen_HK
dc.contributor.authorPowell, DWen_HK
dc.contributor.authorClevers, Hen_HK
dc.contributor.authorLeung, SYen_HK
dc.contributor.authorChen, Xen_HK
dc.date.accessioned2010-09-29T03:56:55Z-
dc.date.available2010-09-29T03:56:55Z-
dc.date.issued2010en_HK
dc.identifier.citationGastroenterology, 2010, v. 139 n. 3, p. 893-903en_HK
dc.identifier.issn0016-5085en_HK
dc.identifier.urihttp://hdl.handle.net/10722/123825-
dc.description.abstractBackground & 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. © 2010 by the AGA Institute.en_HK
dc.languageeng-
dc.publisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastroen_HK
dc.relation.ispartofGastroenterologyen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectBMPen_HK
dc.subjectECMen_HK
dc.subjectHedgehog Signalingen_HK
dc.subjectMMPen_HK
dc.subject.meshCell Communication-
dc.subject.meshColon - metabolism - pathology-
dc.subject.meshEpithelial Cells - metabolism - pathology-
dc.subject.meshHedgehog Proteins - deficiency - genetics - metabolism-
dc.subject.meshIntestinal Mucosa - metabolism - pathology-
dc.titleIndian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during developmenten_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0016-5085&volume=139&issue=3&spage=893&epage=903&date=2010&atitle=Indian+hedgehog+regulates+intestinal+stem+cell+fate+through+epithelial-mesenchymal+interactions+during+development-
dc.identifier.emailLeung, SY:suetyi@hkucc.hku.hken_HK
dc.identifier.authorityLeung, SY=rp00359en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1053/j.gastro.2010.06.014en_HK
dc.identifier.pmid20542037-
dc.identifier.pmcidPMC2930094-
dc.identifier.scopuseid_2-s2.0-77956168783en_HK
dc.identifier.hkuros174354-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77956168783&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume139en_HK
dc.identifier.issue3en_HK
dc.identifier.spage893en_HK
dc.identifier.epage903en_HK
dc.identifier.isiWOS:000281365500031-
dc.publisher.placeUnited Statesen_HK

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