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

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

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)893-903
Number of pages11
JournalGastroenterology
Volume139
Issue number3
DOIs
StatePublished - 2010

Fingerprint

Hedgehogs
Stem Cells
Mucous Membrane
Bone Morphogenetic Proteins
Foster Home Care
Myofibroblasts
Enterocytes
Extracellular Matrix Proteins
Matrix Metalloproteinases
Mesenchymal Stromal Cells
In Situ Hybridization
Extracellular Matrix
Cell Proliferation
Organizations

Keywords

  • BMP
  • ECM
  • Hedgehog Signaling
  • MMP

ASJC Scopus subject areas

  • Gastroenterology
  • Medicine(all)

Cite this

Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. / Kosinski, Cynthia; Stange, Daniel E.; Xu, Chuanrui; Chan, Annie Sy; Ho, Coral; Yuen, Siu Tsan; Mifflin, Randy C.; Powell, Don W.; Clevers, Hans; Leung, Suet Yi; Chen, Xin.

In: Gastroenterology, Vol. 139, No. 3, 2010, p. 893-903.

Research output: Contribution to journalArticle

Kosinski, C, Stange, DE, Xu, C, Chan, AS, Ho, C, Yuen, ST, Mifflin, RC, Powell, DW, Clevers, H, Leung, SY & Chen, X 2010, 'Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development', Gastroenterology, vol. 139, no. 3, pp. 893-903. https://doi.org/10.1053/j.gastro.2010.06.014
Kosinski, Cynthia ; Stange, Daniel E. ; Xu, Chuanrui ; Chan, Annie Sy ; Ho, Coral ; Yuen, Siu Tsan ; Mifflin, Randy C. ; Powell, Don W. ; Clevers, Hans ; Leung, Suet Yi ; Chen, Xin. / Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. In: Gastroenterology. 2010 ; Vol. 139, No. 3. pp. 893-903.
@article{9ebd600f96124bf9bb436689e7e61fef,
title = "Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development",
abstract = "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.",
keywords = "BMP, ECM, Hedgehog Signaling, MMP",
author = "Cynthia Kosinski and Stange, {Daniel E.} and Chuanrui Xu and Chan, {Annie Sy} and Coral Ho and Yuen, {Siu Tsan} and Mifflin, {Randy C.} and Powell, {Don W.} and Hans Clevers and Leung, {Suet Yi} and Xin Chen",
year = "2010",
doi = "10.1053/j.gastro.2010.06.014",
language = "English (US)",
volume = "139",
pages = "893--903",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "3",

}

TY - JOUR

T1 - Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development

AU - Kosinski, Cynthia

AU - Stange, Daniel E.

AU - Xu, Chuanrui

AU - Chan, Annie Sy

AU - Ho, Coral

AU - Yuen, Siu Tsan

AU - Mifflin, Randy C.

AU - Powell, Don W.

AU - Clevers, Hans

AU - Leung, Suet Yi

AU - Chen, Xin

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

KW - BMP

KW - ECM

KW - Hedgehog Signaling

KW - MMP

UR - http://www.scopus.com/inward/record.url?scp=77956168783&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956168783&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2010.06.014

DO - 10.1053/j.gastro.2010.06.014

M3 - Article

VL - 139

SP - 893

EP - 903

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 3

ER -