Home LiteratureArticle Details
PMID: 16987141 Published · ppublish English Journal Article

An enteroendocrine cell-based model for a quiescent intestinal stem cell niche.

Cell proliferation ·Vol. 39 ·No. 5 ·2006-10-00 ·Pages 403-14

Radford IR, Lobachevsky PN

Abstract

We have shown that the kinetics of conversion of intestinal crypt cell populations to a partially or wholly mutant phenotype are consistent with a model in which each crypt contains an infrequently dividing 'deep' stem cell that is the progenitor of several more frequently dividing 'proximate' stem cells. An assumption of our model is that each deep stem cell exists in a growth inhibitory niche. We have used information from the literature to develop a model for a quiescent intestinal stem cell niche. This niche is postulated to be primarily defined by an enteroendocrine cell type that maintains stem cell quiescence by secretion of growth inhibitory peptides such as somatostatin and guanylin/uroguanylin. Consistent with this model, there is evidence that the proteins postulated as defining a growth-inhibitory stem cell niche can act as intestinal tumour suppressors. Confirmation that a growth-inhibitory niche does exist would have important implications for our understanding of intestinal homeostasis and tumorigenesis.

MeSH Terms
Animals Cell Differentiation/physiology Cell Lineage/physiology Enterocytes/cytology,physiology Enteroendocrine Cells/cytology,physiology Gastrointestinal Hormones/metabolism Humans Intestinal Mucosa/cytology Models, Biological Natriuretic Peptides/metabolism Somatostatin/metabolism Stem Cells/cytology,physiology
Chemicals
Gastrointestinal Hormones Natriuretic Peptides guanylin uroguanylin Somatostatin
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Radford I R
South Yarra, Victoria, Australia. ianrradford@optusnet.com.au
Lobachevsky P N
References (106)
106 references, click to expand
  1. [3H]GABA uptake and GABA localization in mucosal endocrine cells of the rat stomach and colon.
    J Auton Nerv Syst. 1994 May;47(3):225-32 PMID: 8014381
  2. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Entero-endocrine cells.
    Am J Anat. 1974 Dec;141(4):503-19 PMID: 4216261
  3. Adenomatous polyposis coli proteins and cell adhesion.
    Curr Opin Cell Biol. 2004 Oct;16(5):528-35 PMID: 15363803
  4. Regulation of neuronal nitric oxide and cyclic GMP formation by Ca2+.
    J Neurochem. 1992 Dec;59(6):2024-9 PMID: 1279121
  5. Expression patterns of Wnt genes in mouse gut development.
    Mech Dev. 2001 Jul;105(1-2):181-4 PMID: 11429295
  6. Neurochemical characterization and distribution of enteric GABAergic neurons and nerve fibres in the human colon.
    J Auton Nerv Syst. 1998 Jan 19;68(1-2):33-42 PMID: 9531443
  7. Osteoblastic cells regulate the haematopoietic stem cell niche.
    Nature. 2003 Oct 23;425(6960):841-6 PMID: 14574413
  8. Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagens.
    Am J Pathol. 1995 Nov;147(5):1416-27 PMID: 7485404
  9. Scanning electron microscopy of isolated epithelium of the murine gastrointestinal tract: morphology of the basal surface and evidence for paracrinelike cells.
    Am J Anat. 1986 Sep;177(1):43-53 PMID: 3776888
  10. Gene expression profiles in normal and cancer cells.
    Science. 1997 May 23;276(5316):1268-72 PMID: 9157888
  11. Expression of guanylin is downregulated in mouse and human intestinal adenomas.
    Biochem Biophys Res Commun. 2000 Jun 24;273(1):225-30 PMID: 10873591
  12. Somatostatin is required for masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth.
    J Clin Invest. 2001 Jun;107(12):1571-80 PMID: 11413165
  13. Ultrastructure of enterochromaffin cells and associated neural and vascular elements in the mouse duodenum.
    Cell Tissue Res. 1985;241(3):557-63 PMID: 4028141
  14. sst2 somatostatin receptor expression reverses tumorigenicity of human pancreatic cancer cells.
    Cancer Res. 1997 Mar 1;57(5):956-62 PMID: 9041201
  15. Intestinal stem cells and mucosal gut development.
    Curr Opin Gastroenterol. 2003 Nov;19(6):583-90 PMID: 15703609
  16. Morphological study of the regeneration mechanism of acetic acid-injured colon crypts in the rat.
    Med Electron Microsc. 2000;33(3):165-71 PMID: 11810475
  17. Development of the pattern of cell renewal in the crypt-villus unit of chimaeric mouse small intestine.
    Development. 1988 Aug;103(4):785-90 PMID: 3248525
  18. Renal effects of uroguanylin and guanylin in vivo.
    Braz J Med Biol Res. 1999 Nov;32(11):1337-44 PMID: 10559834
  19. APC mutations in sporadic colorectal tumors: A mutational "hotspot" and interdependence of the "two hits".
    Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3352-7 PMID: 10737795
  20. Selection of multipotent stem cells during morphogenesis of small intestinal crypts of Lieberkuhn is perturbed by stimulation of Lef-1/beta-catenin signaling.
    J Biol Chem. 2002 May 3;277(18):15843-50 PMID: 11854293
  21. High-intensity p38 kinase activity is critical for p21(cip1) induction and the antiproliferative function of G(i) protein-coupled receptors.
    Mol Pharmacol. 2001 May;59(5):1119-28 PMID: 11306695
  22. Stem cells find their niche.
    Nature. 2001 Nov 1;414(6859):98-104 PMID: 11689954
  23. The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine.
    Br J Cancer. 1998 Oct;78(8):993-1003 PMID: 9792141
  24. Coexistence of proguanylin (1-15) and somatostatin in the gastrointestinal tract.
    J Gastroenterol Hepatol. 1998 Dec;13(12):1225-33 PMID: 9918430
  25. A test of the stochastic theory of stem cell differentiation.
    Biophys J. 1986 Jun;49(6):1223-7 PMID: 3719076
  26. A niche for adult neural stem cells.
    Curr Opin Genet Dev. 2003 Oct;13(5):543-50 PMID: 14550422
  27. Altered stem cell regeneration in irradiated intestinal crypts of senescent mice.
    J Cell Sci. 1998 Aug;111 ( Pt 16):2297-303 PMID: 9683625
  28. Uroguanylin knockout mice have increased blood pressure and impaired natriuretic response to enteral NaCl load.
    J Clin Invest. 2003 Oct;112(8):1244-54 PMID: 14561709
  29. DE-cadherin-mediated cell adhesion is essential for maintaining somatic stem cells in the Drosophila ovary.
    Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14813-8 PMID: 12393817
  30. Application of immunohistochemistry to the isolated mucosa of the mouse gastrointestinal tract, with special reference to somatostatin cells.
    Acta Anat (Basel). 1988;133(3):229-33 PMID: 2906495
  31. Somatostatin inhibits Akt phosphorylation and cell cycle entry, but not p42/p44 mitogen-activated protein (MAP) kinase activation in normal and tumoral pancreatic acinar cells.
    Endocrinology. 2001 Jan;142(1):121-8 PMID: 11145574
  32. Bacterial enterotoxins are associated with resistance to colon cancer.
    Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2695-9 PMID: 12594332
  33. Intestinal crypt properties fit a model that incorporates replicative ageing and deep and proximate stem cells.
    Cell Prolif. 2006 Oct;39(5):379-402 PMID: 16987140
  34. sst2 somatostatin receptor mediates cell cycle arrest and induction of p27(Kip1). Evidence for the role of SHP-1.
    J Biol Chem. 1999 May 21;274(21):15186-93 PMID: 10329727
  35. Intact signaling by transforming growth factor beta is not required for termination of liver regeneration in mice.
    Hepatology. 2004 Nov;40(5):1098-105 PMID: 15389868
  36. Brain somatostatin receptors are up-regulated in somatostatin-deficient mice.
    Mol Endocrinol. 2002 Aug;16(8):1951-63 PMID: 12145348
  37. Negative regulation of beta-catenin signaling by tyrosine phosphatase SHP-1 in intestinal epithelial cells.
    J Biol Chem. 2003 Apr 18;278(16):14274-83 PMID: 12571228
  38. The intestinal epithelial stem cell.
    Bioessays. 2002 Jan;24(1):91-8 PMID: 11782954
  39. Expression of notch receptors and ligands in the adult gut.
    J Histochem Cytochem. 2004 Apr;52(4):509-16 PMID: 15034002
  40. Somatostatin and its receptor family.
    Front Neuroendocrinol. 1999 Jul;20(3):157-98 PMID: 10433861
  41. Identification of the haematopoietic stem cell niche and control of the niche size.
    Nature. 2003 Oct 23;425(6960):836-41 PMID: 14574412
  42. Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.
    Cancer Res. 2000 Sep 15;60(18):5151-7 PMID: 11016642
  43. The laminins: role in intestinal morphogenesis and differentiation.
    Ann N Y Acad Sci. 1998 Nov 17;859:46-64 PMID: 9928369
  44. Restoration of full-length adenomatous polyposis coli (APC) protein in a colon cancer cell line enhances cell adhesion.
    J Cell Sci. 2004 Jan 26;117(Pt 3):427-39 PMID: 14679305
  45. Guanylin and related peptides.
    J Physiol Pharmacol. 2001 Sep;52(3):351-75 PMID: 11596856
  46. Interactions between laminin and epithelial cells in intestinal health and disease.
    Expert Rev Mol Med. 2001 Sep 28;3(24):1-18 PMID: 14585148
  47. Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation.
    Am J Pathol. 2002 Dec;161(6):2169-78 PMID: 12466132
  48. Time of origin of neurons in the murine enteric nervous system: sequence in relation to phenotype.
    J Comp Neurol. 1991 Dec 22;314(4):789-98 PMID: 1816276
  49. Expression of functional GABAA receptors in cholecystokinin-secreting gut neuroendocrine murine STC-1 cells.
    J Physiol. 1998 Aug 1;510 ( Pt 3):805-14 PMID: 9660895
  50. Neuropeptides, via specific receptors, regulate T cell adhesion to fibronectin.
    J Immunol. 1998 Jan 15;160(2):993-1000 PMID: 9551939
  51. Cellular localization of cyclo-oxygenase isozymes in Crohn's disease and colorectal cancer.
    Int J Colorectal Dis. 1999 Nov;14(4-5):212-8 PMID: 10647629
  52. Control of neuronal nitric oxide synthase and brain-derived neurotrophic factor levels by GABA-A receptors in the developing rat cortex.
    Brain Res Dev Brain Res. 2003 Nov 12;145(2):185-95 PMID: 14604759
  53. Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer.
    Cancer Res. 1996 Apr 15;56(8):1823-7 PMID: 8620499
  54. Detection of nitric oxide synthase (NOS) in somatostatin-producing cells of human and murine stomach and pancreas.
    J Histochem Cytochem. 1996 Apr;44(4):339-46 PMID: 8601693
  55. COX-2 is expressed in human pulmonary, colonic, and mammary tumors.
    Cancer. 2000 Dec 15;89(12):2637-45 PMID: 11135226
  56. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.
    Cell. 2004 Sep 3;118(5):635-48 PMID: 15339667
  57. Myenteric plexus destruction alters morphology of rat intestine.
    Gastroenterology. 1993 Oct;105(4):1017-28 PMID: 8405844
  58. Disruption of the guanylyl cyclase-C gene leads to a paradoxical phenotype of viable but heat-stable enterotoxin-resistant mice.
    J Clin Invest. 1997 Sep 15;100(6):1590-5 PMID: 9294128
  59. Migration and turnover of entero-endocrine and caveolated cells in the epithelium of the descending colon, as shown by radioautography after continuous infusion of 3H-thymidine into mice.
    Am J Anat. 1979 Dec;156(4):431-51 PMID: 525623
  60. Differentiation hotspots: the deterioration of hierarchy and stochasm.
    Blood Cells Mol Dis. 2004 Jan-Feb;32(1):34-41 PMID: 14757410
  61. Cell migration velocities in the crypts of the small intestine after cytotoxic insult are not dependent on mitotic activity.
    Cell Tissue Kinet. 1986 Nov;19(6):601-10 PMID: 3026633
  62. Peptide growth factors in the intestine.
    Eur J Gastroenterol Hepatol. 2001 Jul;13(7):763-70 PMID: 11474304
  63. Neuronal nitric oxide synthase: a substrate for SHP-1 involved in sst2 somatostatin receptor growth inhibitory signaling.
    FASEB J. 2001 Oct;15(12):2300-2 PMID: 11511520
  64. SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway.
    Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9719-23 PMID: 11481457
  65. Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells. Involvement of phosphatidylinositol 3-kinase/Akt pathway.
    J Biol Chem. 2001 Dec 28;276(52):48997-9002 PMID: 11585835
  66. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells.
    Science. 2004 May 28;304(5675):1338-40 PMID: 15060285
  67. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.
    Nat Genet. 2004 Oct;36(10):1117-21 PMID: 15378062
  68. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.
    Cell. 2004 Jul 23;118(2):149-61 PMID: 15260986
  69. The neurotransmitter gamma-aminobutyric acid is an inhibitory regulator for the migration of SW 480 colon carcinoma cells.
    Cancer Res. 2002 Nov 15;62(22):6467-9 PMID: 12438237
  70. Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium.
    EMBO J. 2002 Dec 2;21(23):6338-47 PMID: 12456641
  71. The "normal" endocrine cell of the gut: changing concepts and new evidences.
    Ann N Y Acad Sci. 2004 Apr;1014:1-12 PMID: 15153415
  72. The small intestine as a model for evaluating adult tissue stem cell drug targets.
    Cell Prolif. 2003 Jun;36(3):115-29 PMID: 12814429
  73. The gastrointestinal stem cell.
    Cell Prolif. 2004 Feb;37(1):35-53 PMID: 14871236
  74. Myofibroblasts. II. Intestinal subepithelial myofibroblasts.
    Am J Physiol. 1999 Aug;277(2):C183-201 PMID: 10444394
  75. Localization of [3H]GABA-labelled nerve fibre networks in the rat intestinal mucosa.
    J Auton Nerv Syst. 1991 Jun 15;34(2-3):195-200 PMID: 1655859
  76. Why is cyclooxygenase-2 expressed in neuroendocrine cells of the human alimentary tract?
    Pathol Int. 1997 Dec;47(12):889-91 PMID: 9503473
  77. Minireview: Development and differentiation of gut endocrine cells.
    Endocrinology. 2004 Jun;145(6):2639-44 PMID: 15044355
  78. Disruption of cyclooxygenase-1 gene results in an impaired response to radiation injury.
    Am J Physiol Gastrointest Liver Physiol. 2000 Nov;279(5):G858-65 PMID: 11052981
  79. Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract.
    J Neurosci. 1996 Apr 1;16(7):2352-64 PMID: 8601815
  80. Uroguanylin: gene structure, expression, processing as a peptide hormone, and co-storage with somatostatin in gastrointestinal D-cells.
    Regul Pept. 1998 Feb 27;73(3):165-76 PMID: 9556079
  81. Nitric oxide regulates the release of somatostatin from cultured gastric rabbit primary D-cells.
    Gastroenterology. 2002 Aug;123(2):566-76 PMID: 12145809
  82. Regional variability of colonocyte growth and differentiation in the rat.
    Anat Rec. 1992 Jul;233(3):409-14 PMID: 1376970
  83. Somatostatin receptor (SSTR) expression and function in normal and leukaemic T-cells. Evidence for selective effects on adhesion to extracellular matrix components via SSTR2 and/or 3.
    Clin Exp Immunol. 2001 Jul;125(1):71-9 PMID: 11472428
  84. The crypt cycle in mouse small intestinal epithelium.
    J Cell Sci. 1994 Dec;107 ( Pt 12):3271-9 PMID: 7535783
  85. C-terminal region of human somatostatin receptor 5 is required for induction of Rb and G1 cell cycle arrest.
    Mol Endocrinol. 1999 Jan;13(1):82-90 PMID: 9892014
  86. Control of endodermal endocrine development by Hes-1.
    Nat Genet. 2000 Jan;24(1):36-44 PMID: 10615124
  87. Recruitment of cells in the small intestine into rapid cell cycle by small doses of external gamma or internal beta-radiation.
    Int J Radiat Biol Relat Stud Phys Chem Med. 1985 Sep;48(3):361-9 PMID: 3875577
  88. Somatostatin receptor subtype 2 mediates somatostatin inhibition of ion secretion in rat distal colon.
    Gastroenterology. 1996 Aug;111(2):325-33 PMID: 8690197
  89. Guanylin mRNA expression in human intestine and colorectal adenocarcinoma.
    Lab Invest. 1998 Jan;78(1):101-8 PMID: 9461126
  90. The myenteric plexus regulates cell growth in rat jejunum.
    J Auton Nerv Syst. 1990 Dec;31(3):219-29 PMID: 2084186
  91. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine.
    Science. 2004 Mar 12;303(5664):1684-6 PMID: 15017003
  92. Nitric oxide is a regulator of hematopoietic stem cell activity.
    Mol Ther. 2004 Aug;10(2):241-8 PMID: 15294171
  93. Asymmetric cell division.
    Curr Opin Cell Biol. 2004 Apr;16(2):195-205 PMID: 15196564
  94. The stem state: plasticity is essential, whereas self-renewal and hierarchy are optional.
    Stem Cells. 2005 Jun-Jul;23(6):719-26 PMID: 15917468
  95. Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation.
    J Clin Invest. 2004 Dec;114(11):1676-85 PMID: 15578100
  96. Mutational analysis of the tyrosine kinome in colorectal cancers.
    Science. 2003 May 9;300(5621):949 PMID: 12738854
  97. Modulation of specific intestinal epithelial progenitors by enteric neurons.
    Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12497-502 PMID: 11572941
  98. Anti-migratory and anti-invasive effect of somatostatin in human neuroblastoma cells: involvement of Rac and MAP kinase activity.
    J Biol Chem. 2003 Oct 17;278(42):40601-6 PMID: 12902325
  99. Apobec-1 protects intestine from radiation injury through posttranscriptional regulation of cyclooxygenase-2 expression.
    Gastroenterology. 2004 Oct;127(4):1139-49 PMID: 15480992
  100. Peptide YY expression is an early event in colonic endocrine cell differentiation: evidence from normal and transgenic mice.
    Development. 1996 Apr;122(4):1157-63 PMID: 8620842
  101. The distribution of endocrine cells along the mouse intestine: a quantitative immunocytochemical study.
    Virchows Arch B Cell Pathol Incl Mol Pathol. 1988;56(3):191-9 PMID: 2906190
  102. Somatostatin cell processes as pathways for paracrine secretion.
    Science. 1979 Sep 28;205(4413):1393-5 PMID: 382360
  103. Transcriptional activation of mouse sst2 somatostatin receptor promoter by transforming growth factor-beta. Involvement of Smad4.
    J Biol Chem. 2001 Apr 20;276(16):13461-8 PMID: 11278805
  104. Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia.
    J Cell Sci. 1995 Jun;108 ( Pt 6):2261-71 PMID: 7673346
  105. Colocalization of NO and VIP in neurons of the submucous plexus in the rat intestine.
    Peptides. 2002 Dec;23(12):2245-50 PMID: 12535705
  106. Mutation selection and the natural history of cancer.
    Nature. 1975 May 15;255(5505):197-200 PMID: 1143315
Article Info
Journal
Cell proliferation
Abbr.
Cell Prolif
ISSN
0960-7722
DOI
10.1111/j.1365-2184.2006.00396.x
Email
ianrradford@optusnet.com.au
Published
2006-10-00
Pages
403-14
Language
English
Region
England
NLM ID
9105195
PMCID
PMC6496364
Subset
IM
External Links
PubMed source DOI: 10.1111/j.1365-2184.2006.00396.x PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2