Gastroenterology
Volume 139, Issue 3 , Pages 893-903 , September 2010

Indian Hedgehog Regulates Intestinal Stem Cell Fate Through Epithelial−Mesenchymal Interactions During Development

  • Cynthia Kosinski

      Affiliations

    • Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California
    • ,
  • Daniel E. Stange

      Affiliations

    • Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
    • ,
  • Chuanrui Xu

      Affiliations

    • Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California
    • ,
  • Annie Sy Chan

      Affiliations

    • Department of Pathology and Center for Cancer Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
    • ,
  • Coral Ho

      Affiliations

    • Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California
    • ,
  • Siu Tsan Yuen

      Affiliations

    • Department of Pathology and Center for Cancer Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
    • ,
  • Randy C. Mifflin

      Affiliations

    • Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas
    • ,
  • Don W. Powell

      Affiliations

    • Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas
    • ,
  • Hans Clevers

      Affiliations

    • Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
    • ,
  • Suet Yi Leung

      Affiliations

    • Department of Pathology and Center for Cancer Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
    • Corresponding Author InformationSuet-Yi Leung, MD, FRCPath, Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. fax: (852) 2872-5197
    • ,
  • Xin Chen

      Affiliations

    • Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California
    • Corresponding Author InformationReprint requests Address requests for reprints to: Xin Chen, PhD, Department of Bioengineering and Therapeutic Sciences, University of California, 513 Parnassus Avenue, San Francisco, California 94143. fax: (415) 502-4322

Received 18 December 2009 ,Accepted 1 June 2010.

References 

  1. Barker N, van de Wetering M, Clevers H. The intestinal stem cell. Genes Dev. 2008;22:1856–1864
  2. van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol. 2009;71:241–260
  3. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–1007
  4. Sangiorgi E, Capecchi MR. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet. 2008;40:915–920
  5. Walker MR, Patel KK, Stappenbeck TS. The stem cell niche. J Pathol. 2009;217:169–180
  6. Powell DW, Adegboyega PA, Di Mari JF, et al. Epithelial cells and their neighbors I (Role of intestinal myofibroblasts in development, repair, and cancer). Am J Physiol Gastrointest Liver Physiol. 2005;289:G2–G7
  7. He XC, Zhang J, Tong WG, et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet. 2004;36:1117–1121
  8. Kosinski C, Li VS, Chan AS, et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A. 2007;104:15418–15423
  9. van den Brink GR. Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol Rev. 2007;87:1343–1375
  10. Ramalho-Santos M, Melton DA, McMahon AP. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development. 2000;127:2763–2772
  11. Kolterud A, Grosse AS, Zacharias WJ, et al. Paracrine Hedgehog signaling in stomach and intestine: new roles for hedgehog in gastrointestinal patterning. Gastroenterology. 2009;137:618–628
  12. Madison BB, Braunstein K, Kuizon E, et al. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development. 2005;132:279–289
  13. van Dop WA, Uhmann A, Wijgerde M, et al. Depletion of the colonic epithelial precursor cell compartment upon conditional activation of the hedgehog pathway. Gastroenterology. 2009;136:2195–2203e1–e7
  14. Razzaque MS, Soegiarto DW, Chang D, et al. Conditional deletion of Indian hedgehog from collagen type 2alpha1-expressing cells results in abnormal endochondral bone formation. J Pathol. 2005;207:453–461
  15. Madison BB, Dunbar L, Qiao XT, et al. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J Biol Chem. 2002;277:33275–33283
  16. Long F, Zhang XM, Karp S, et al. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development. 2001;128:5099–5108
  17. van der Flier LG, Haegebarth A, Stange DE, et al. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology. 2009;137:15–17
  18. van den Brink GR, Bleuming SA, Hardwick JC, et al. Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat Genet. 2004;36:277–282
  19. Lauth M, Bergstrom A, Shimokawa T, et al. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci U S A. 2007;104:8455–8460
  20. Wong MH, Rubinfeld B, Gordon JI. Effects of forced expression of an NH2-terminal truncated beta-Catenin on mouse intestinal epithelial homeostasis. J Cell Biol. 1998;141:765–777
  21. van de Wetering M, Sancho E, Verweij C, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002;111:241–250
  22. Zacharias WJ, Li X, Madison BB, et al. Hedgehog is an anti-inflammatory epithelial signal for the intestinal lamina propria. Gastroenterology. 2010;138:2368–23772377.e1–e4
  23. Varnat F, Heggeler BB, Grisel P, et al. PPARbeta/delta regulates paneth cell differentiation via controlling the hedgehog signaling pathway. Gastroenterology. 2006;131:538–553
  24. Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455:406–410
  25. van der Flier LG, van Gijn ME, Hatzis P, et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell. 2009;136:903–912
  26. Haramis AP, Begthel H, van den Born M, et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science. 2004;303:1684–1686
  27. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell. 2008;15:801–812
  28. Lauth M, Toftgard R. The Hedgehog pathway as a drug target in cancer therapy. Curr Opin Invest Drugs. 2007;8:457–461
  29. Chatel G, Ganeff C, Boussif N, et al. Hedgehog signaling pathway is inactive in colorectal cancer cell lines. Int J Cancer. 2007;121:2622–2627
  30. Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425:846–851
  31. Qualtrough D, Buda A, Gaffield W, et al. Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment. Int J Cancer. 2004;110:831–837

 Transcript profiling: The raw data of microarray experiment are available at Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/projects/geo) under the accession number of GSE18393.

 Conflicts of interest The authors disclose no conflicts.

 Funding 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.

PII: S0016-5085(10)00873-5

doi: 10.1053/j.gastro.2010.06.014

Gastroenterology
Volume 139, Issue 3 , Pages 893-903 , September 2010

Article Tools

* Image Usage & Resolution