Stem cells, self-renewal, and differentiation in the intestinal epithelium.

The mammalian intestine is covered by a single layer of epithelial cells that is renewed every 4-5 days. This high cell turnover makes it a very attractive and comprehensive adult organ system for the study of cell proliferation and differentiation. The intestine is composed of proliferative crypts, which contain intestinal stem cells, and villi, which contain differentiated specialized cell types. Through the recent identification of Lgr5, an intestinal stem cell marker, it is now possible to visualize stem cells and study their behavior and differentiation in a much broader context. In this review we describe the identification of intestinal stem cells. We also discuss genetic studies that have helped to elucidate those signals important for progenitor cells to differentiate into one of the specialized intestinal epithelial cell types. These studies describe a genetic hierarchy responsible for cell fate commitment in normal gut physiology. Where relevant we also mention aberrant deregulation of these molecular pathways that results in colon cancer.

[1]  C. Potten,et al.  CONTINUOUS LABELLING STUDIES ON MOUSE SKIN AND INTESTINE , 1974, Cell and tissue kinetics.

[2]  C. P. Leblond,et al.  Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. , 1974, The American journal of anatomy.

[3]  C. P. Leblond,et al.  Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. I. Columnar cell. , 1974, The American journal of anatomy.

[4]  A. Cairnie,et al.  FISSION OF CRYPTS IN THE SMALL INTESTINE OF THE IRRADIATED MOUSE , 1975, Cell and tissue kinetics.

[5]  C. Potten,et al.  Extreme sensitivity of some intestinal crypt cells to X and γ irradiation , 1977, Nature.

[6]  R. Schofield.  The relationship between the spleen colony-forming cell and the haemopoietic stem cell. , 1978, Blood cells.

[7]  H Cheng,et al.  The stem-cell zone of the small intestinal epithelium. I. Evidence from Paneth cells in the adult mouse. , 1981, The American journal of anatomy.

[8]  M. Bjerknes,et al.  The stem-cell zone of the small intestinal epithelium. III. Evidence from columnar, enteroendocrine, and mucous cells in the adult mouse. , 1981, The American journal of anatomy.

[9]  B. A. J. Ponder,et al.  A clonal marker induced by mutation in mouse intestinal epithelium , 1988, Nature.

[10]  B. Ponder,et al.  Development of the pattern of cell renewal in the crypt-villus unit of chimaeric mouse small intestine. , 1988, Development.

[11]  C. Fuller,et al.  Crypt restricted heterogeneity of goblet cell mucus glycoprotein in histologically normal human colonic mucosa: a potential marker of somatic mutation. , 1990, British Journal of Cancer.

[12]  B. Vogelstein,et al.  A genetic model for colorectal tumorigenesis , 1990, Cell.

[13]  D. Winton,et al.  Stem-cell organization in mouse small intestine , 1990, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[14]  H. Pitot,et al.  A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. , 1990, Science.

[15]  K. Kinzler,et al.  Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Kinzler,et al.  Erratum: Multiple Intestinal Neoplasia Caused By a Mutation in the Murine Homolog of the APC Gene , 1992, Science.

[17]  Bert Vogelstein,et al.  APC mutations occur early during colorectal tumorigenesis , 1992, Nature.

[18]  P. Hall,et al.  Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. , 1994, Journal of cell science.

[19]  M. Fukayama,et al.  Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. , 1994, Cancer research.

[20]  S. Minoguchi,et al.  Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-Jκ/Su(H) , 1995, Current Biology.

[21]  B. Hogan,et al.  PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. , 1996, Development.

[22]  J. Heath,et al.  EPITHELIAL CELL MIGRATION IN THE INTESTINE , 1996, Cell biology international.

[23]  W. Bodmer,et al.  Polyclonal Origin of Colonic Adenomas in an XO/XY Patient with FAP , 1996, Science.

[24]  M. Tsai,et al.  Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. , 1997, Genes & development.

[25]  K. Kinzler,et al.  Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC−/− Colon Carcinoma , 1997, Science.

[26]  Hans Clevers,et al.  Activation of β-Catenin-Tcf Signaling in Colon Cancer by Mutations in β-Catenin or APC , 1997, Science.

[27]  Paul Polakis,et al.  Stabilization of β-Catenin by Genetic Defects in Melanoma Cell Lines , 1997, Science.

[28]  K. Kaestner,et al.  The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation. , 1997, Genes & development.

[29]  Hans Clevers,et al.  Armadillo Coactivates Transcription Driven by the Product of the Drosophila Segment Polarity Gene dTCF , 1997, Cell.

[30]  T. Noda,et al.  Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. , 1997, Science.

[31]  Hans Clevers,et al.  Drosophila Tcf and Groucho interact to repress Wingless signalling activity , 1998, Nature.

[32]  D. Hougaard,et al.  Pax 4 and 6 regulate gastrointestinal endocrine cell development , 1998, Mechanisms of Development.

[33]  Hans Clevers,et al.  Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4 , 1998, Nature Genetics.

[34]  L. Aaltonen,et al.  Mutations in the SMAD4/DPC4 gene in juvenile polyposis. , 1998, Science.

[35]  B. Sauer.  Inducible gene targeting in mice using the Cre/lox system. , 1998, Methods.

[36]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[37]  Hans Clevers,et al.  The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors , 1998, Nature.

[38]  D. Drucker,et al.  Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription. , 1999, Molecular endocrinology.

[39]  S. Artavanis-Tsakonas,et al.  Notch Signaling : Cell Fate Control and Signal Integration in Development , 1999 .

[40]  M. Taketo,et al.  Intestinal polyposis in mice with a dominant stable mutation of the β‐catenin gene , 1999, The EMBO journal.

[41]  Philippe Soriano.  Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[42]  H Cheng,et al.  Clonal analysis of mouse intestinal epithelial progenitors. , 1999, Gastroenterology.

[43]  S. Karam.  Lineage commitment and maturation of epithelial cells in the gut. , 1999, Frontiers in bioscience : a journal and virtual library.

[44]  A B West,et al.  Myofibroblasts. II. Intestinal subepithelial myofibroblasts. , 1999, American journal of physiology. Cell physiology.

[45]  H Clevers,et al.  Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium. , 1999, The American journal of pathology.

[46]  H. Arnold,et al.  Targeted disruption of the homeobox transcription factor Nkx2-3 in mice results in postnatal lethality and abnormal development of small intestine and spleen. , 1999, Development.

[47]  C. Betsholtz,et al.  Abnormal gastrointestinal development in PDGF-A and PDGFR-(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. , 2000, Development.

[48]  K. Chawengsaksophak,et al.  Homeobox genes and gut development , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[49]  David I. Smith,et al.  Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating β-catenin/TCF signalling , 2000, Nature Genetics.

[50]  David I. Smith,et al.  Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling (vol 26, pg 146, 2000) , 2000 .

[51]  Ryoichiro Kageyama,et al.  Control of endodermal endocrine development by Hes-1 , 2000, Nature Genetics.

[52]  D. Roberts,et al.  Molecular mechanisms of development of the gastrointestinal tract , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[53]  D. Melton,et al.  Hedgehog signals regulate multiple aspects of gastrointestinal development. , 2000, Development.

[54]  J. Gordon,et al.  The intestinal stem cell niche: There grows the neighborhood , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[55]  S. Tavaré,et al.  Investigating stem cells in human colon by using methylation patterns , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Victor E. Velculescu,et al.  Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis , 2001, Nature Genetics.

[57]  H. Zoghbi,et al.  Requirement of Math1 for Secretory Cell Lineage Commitment in the Mouse Intestine , 2001, Science.

[58]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[59]  W F Bodmer,et al.  Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. , 2001, American journal of human genetics.

[60]  I. Kola,et al.  Inactivation of the transcription factor Elf3 in mice results in dysmorphogenesis and altered differentiation of intestinal epithelium. , 2002, Gastroenterology.

[61]  Kan Yang,et al.  Colorectal Cancer in Mice Genetically Deficient in the Mucin Muc2 , 2002, Science.

[62]  Tony Pawson,et al.  β-Catenin and TCF Mediate Cell Positioning in the Intestinal Epithelium by Controlling the Expression of EphB/EphrinB , 2002, Cell.

[63]  Nathalie Perreault,et al.  The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. , 2002, Development.

[64]  Christopher S Potten,et al.  Intestinal stem cells protect their genome by selective segregation of template DNA strands. , 2002, Journal of cell science.

[65]  Hans Clevers,et al.  The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells , 2002, Cell.

[66]  Isabelle Duluc,et al.  Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium , 2002, The EMBO journal.

[67]  Christopher S Potten,et al.  The intestinal epithelial stem cell. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[68]  J. Dick,et al.  Breast cancer stem cells revealed , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Hans Clevers,et al.  Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. , 2003, Genes & development.

[70]  Laura C. Greaves,et al.  Mitochondrial DNA mutations in human colonic crypt stem cells. , 2003, The Journal of clinical investigation.

[71]  Jason C Mills,et al.  Molecular features of adult mouse small intestinal epithelial progenitors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[72]  Pauline Chu,et al.  Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[73]  S. Lakhani,et al.  X-inactivation patch size in human female tissue confounds the assessment of tumor clonality , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[74]  Jay S. Fine,et al.  Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation* , 2004, Journal of Biological Chemistry.

[75]  Ian P Newton,et al.  Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. , 2004, Genes & development.

[76]  Daniel Metzger,et al.  Tissue‐specific and inducible Cre‐mediated recombination in the gut epithelium , 2004, Genesis.

[77]  Susan E. Schonhoff,et al.  Minireview: Development and differentiation of gut endocrine cells. , 2004, Endocrinology.

[78]  Hans Clevers,et al.  SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes , 2004, The Journal of cell biology.

[79]  R. Nusse,et al.  The Wnt signaling pathway in development and disease. , 2004, Annual review of cell and developmental biology.

[80]  Ossama Tawfik,et al.  BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt–β-catenin signaling , 2004, Nature Genetics.

[81]  J. Keller,et al.  Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon. , 2003, Gastroenterology.

[82]  O. Sansom,et al.  Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. , 2004, Gastroenterology.

[83]  Francois Pognan,et al.  Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[84]  Hans Clevers,et al.  De Novo Crypt Formation and Juvenile Polyposis on BMP Inhibition in Mouse Intestine , 2004, Science.

[85]  Riccardo Fodde,et al.  APC dosage effects in tumorigenesis and stem cell differentiation. , 2004, The International journal of developmental biology.

[86]  H. Okano,et al.  Hes1-deficient mice show precocious differentiation of Paneth cells in the small intestine. , 2005, Biochemical and biophysical research communications.

[87]  S. Artavanis-Tsakonas,et al.  Notch signals control the fate of immature progenitor cells in the intestine , 2005, Nature.

[88]  Hans Clevers,et al.  Expression pattern of Wnt signaling components in the adult intestine. , 2005, Gastroenterology.

[89]  Neil Vargesson,et al.  Delta-Notch signalling controls commitment to a secretory fate in the zebrafish intestine , 2005, Development.

[90]  D. Melton,et al.  Direct regulation of intestinal fate by Notch. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[91]  A. Sbarbati,et al.  A new fate for old cells: brush cells and related elements , 2005, Journal of anatomy.

[92]  Takeshi Oshima,et al.  Mitogenic Influence of Human R-Spondin1 on the Intestinal Epithelium , 2005, Science.

[93]  J. Dick,et al.  Cancer stem cells: lessons from leukemia. , 2005, Trends in cell biology.

[94]  H. Zoghbi,et al.  Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. , 2005, Genes & development.

[95]  H. Clevers,et al.  Wnt signalling induces maturation of Paneth cells in intestinal crypts , 2005, Nature Cell Biology.

[96]  J. Massagué,et al.  Smad transcription factors. , 2005, Genes & development.

[97]  D. Gumucio,et al.  Epithelial hedgehog signals pattern the intestinal crypt-villus axis , 2005, Development.

[98]  Pierre Laurent-Puig,et al.  Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine , 2005, Development.

[99]  Hans Clevers,et al.  Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells , 2005, Nature.

[100]  M. Washington,et al.  Mtgr1 Is a Transcriptional Corepressor That Is Required for Maintenance of the Secretory Cell Lineage in the Small Intestine , 2005, Molecular and Cellular Biology.

[101]  H. Clevers,et al.  Wnt signaling in the intestinal epithelium: from endoderm to cancer. , 2005, Genes & development.

[102]  Yuzhu Tang,et al.  Epimorphin(-/-) mice have increased intestinal growth, decreased susceptibility to dextran sodium sulfate colitis, and impaired spermatogenesis. , 2006, The Journal of clinical investigation.

[103]  E. Fuchs,et al.  Protein Tyrosine Kinase 6 Negatively Regulates Growth and Promotes Enterocyte Differentiation in the Small Intestine , 2006, Molecular and Cellular Biology.

[104]  Hans Clevers,et al.  Wnt/β-Catenin Signaling in Development and Disease , 2006, Cell.

[105]  E. Ukkonen,et al.  Genome-wide Prediction of Mammalian Enhancers Based on Analysis of Transcription-Factor Binding Affinity , 2006, Cell.

[106]  M. Bjerknes,et al.  Intestinal epithelial stem cells and progenitors. , 2006, Methods in enzymology.

[107]  H. Clevers,et al.  Rapid Loss of Intestinal Crypts upon Conditional Deletion of the Wnt/Tcf-4 Target Gene c-Myc , 2006, Molecular and Cellular Biology.

[108]  Wangxue Chen,et al.  Intestinal M cells: the fallible sentinels? , 2007, World journal of gastroenterology.

[109]  B. Hadland,et al.  Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE , 2006, Development.

[110]  L. Ricci-Vitiani,et al.  Identification and expansion of human colon-cancer-initiating cells , 2007, Nature.

[111]  Suet Yi Leung,et al.  Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors , 2007, Proceedings of the National Academy of Sciences.

[112]  Julie A. Wilkins,et al.  Myc deletion rescues Apc deficiency in the small intestine , 2007, Nature.

[113]  J. Dick,et al.  A human colon cancer cell capable of initiating tumour growth in immunodeficient mice , 2007, Nature.

[114]  Philippe Blache,et al.  Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium , 2007, The Journal of cell biology.

[115]  Riccardo Fodde,et al.  Wnt/β-catenin signaling in cancer stemness and malignant behavior , 2007 .

[116]  Hans Clevers,et al.  SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. , 2006, Gastroenterology.

[117]  H. Clevers,et al.  Identification of stem cells in small intestine and colon by marker gene Lgr5 , 2007, Nature.

[118]  Aleksandar Dakic,et al.  Tumor Growth Need Not Be Driven by Rare Cancer Stem Cells , 2007, Science.

[119]  Simon Tavaré,et al.  The Stem Cell Population of the Human Colon Crypt: Analysis via Methylation Patterns , 2007, PLoS Comput. Biol..

[120]  Joerg Huelsken,et al.  Wnt/β-Catenin Is Essential for Intestinal Homeostasis and Maintenance of Intestinal Stem Cells , 2007, Molecular and Cellular Biology.

[121]  S. McWeeney,et al.  Serial analysis of chromatin occupancy identifies β-catenin target genes in colorectal carcinoma cells , 2007, Proceedings of the National Academy of Sciences.

[122]  J. Lloreta,et al.  EphB–ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells , 2007, Nature Genetics.

[123]  H. Clevers,et al.  The Intestinal Wnt/TCF Signature. , 2007, Gastroenterology.

[124]  P. Hertzog,et al.  TGF-betaRII rescues development of small intestinal epithelial cells in Elf3-deficient mice. , 2007, Gastroenterology.

[125]  Hans Clevers,et al.  Genome-Wide Pattern of TCF7L2/TCF4 Chromatin Occupancy in Colorectal Cancer Cells , 2008, Molecular and Cellular Biology.

[126]  H. Morreau,et al.  Cross-species comparison of human and mouse intestinal polyps reveals conserved mechanisms in adenomatous polyposis coli (APC)-driven tumorigenesis. , 2008, The American journal of pathology.

[127]  Lori Sussel,et al.  Nkx2.2 regulates cell fate choice in the enteroendocrine cell lineages of the intestine. , 2008, Developmental biology.

[128]  Hans Clevers,et al.  Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2 , 2008, EMBO reports.