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Intestinal stem cells and epithelial–mesenchymal interactions in the crypt and stem cell niche

  • Anisa Shaker
    Affiliations
    Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, Mo
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  • Deborah C. Rubin
    Correspondence
    Reprint requests: Deborah C. Rubin, MD, Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8124, Saint Louis, MO 63110
    Affiliations
    Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, Mo

    Department of Developmental Biology, Washington University School of Medicine, Saint Louis, Mo
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      The intestinal epithelium contains a rapidly proliferating and perpetually differentiating epithelium. The principal functional unit of the small intestine is the crypt–villus axis. Stem cells located in the crypts of Lieberkühn give rise to proliferating progenitor or transit amplifying cells that differentiate into the 4 major epithelial cell types. The study of adult gastrointestinal tract stem cells has progressed rapidly with the recent discovery of several putative stem cell markers. Substantial evidence suggests 2 populations of stem cells: long-term quiescent (reserved) and actively cycling (primed) stem cells. These cells are in adjoining locations and are presumably maintained by the secretion of specific proteins generated in a unique microenvironment or stem cell niche surrounding each population. The relationship between these 2 populations, as well as the cellular sources and composition of the surrounding environment, remains to be defined, and is an active area of research. In this review, we will outline progress in identifying stem cells and in defining epithelial–mesenchymal interactions in the crypt. We will summarize early advances using stem cells for therapy of gastrointestinal disorders.

      Abbreviations:

      Ascl2 (achaete scutelike 2), BMP (bone morphogenetic protein), CBC (crypt base columnar), GFP (green fluorescent protein), Hh (Hedgehog), ISC (intestinal stem cell), Lgr (leucine-rich repeat containing G-protein-coupled receptor), mRNA (messenger RNA), MSC (mesenchymal stem cell), Olfm4 (olfactomedin 4), sFRP-5 (secreted frizzled-related protein 5)
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      References

        • Rubin D.C.
        Small intestine: anatomy and structural anomalies.
        in: Yamada T. Textbook of gastroenterology. Wiley-Blackwell, Chichester, West Sussex, UK2009: 1085-1107
        • Mills J.C.
        • Gordon J.I.
        The intestinal stem cell niche: there grows the neighborhood.
        Proc Natl Acad Sci U S A. 2001; 98: 12334-12336
        • Sancho E.
        • Batlle E.
        • Clevers H.
        Live and let die in the intestinal epithelium.
        Curr Opin Cell Biol. 2003; 15: 763-770
        • Bjerknes M.
        • Cheng H.
        Intestinal epithelial stem cells and progenitors.
        Methods Enzymol. 2006; 419: 337-383
        • Abud H.E.
        • Watson N.
        • Heath J.K.
        Growth of intestinal epithelium in organ culture is dependent on EGF signalling.
        Exp Cell Res. 2005; 303: 252-262
        • Li L.
        • Clevers H.
        Coexistence of quiescent and active adult stem cells in mammals.
        Science. 2010; 327: 542-545
        • Scoville D.H.
        • Sato T.
        • He X.C.
        • Li L.
        Current view: intestinal stem cells and signaling.
        Gastroenterology. 2008; 134: 849-864
        • Bjerknes M.
        • Cheng H.
        The stem-cell zone of the small intestinal epithelium. IV. Effects of resecting 30% of the small intestine.
        Am J Anat. 1981; 160: 93-103
        • Haegebarth A.
        • Clevers H.
        Wnt signaling, lgr5, and stem cells in the intestine and skin.
        Am J Pathol. 2009; 174: 715-721
        • May R.
        • Sureban S.M.
        • Hoang N.
        • et al.
        Doublecortin and CaM kinase-like-1 and leucine-rich-repeat-containing G-protein-coupled receptor mark quiescent and cycling intestinal stem cells, respectively.
        Stem Cells. 2009; 27: 2571-2579
        • Potten C.S.
        • Booth C.
        • Pritchard D.M.
        The intestinal epithelial stem cell: the mucosal governor.
        Int J Exp Pathol. 1997; 78: 219-243
        • Batlle E.
        A new identity for the elusive intestinal stem cell.
        Nat Genet. 2008; 40: 818-819
        • Potten C.S.
        • Owen G.
        • Booth D.
        Intestinal stem cells protect their genome by selective segregation of template DNA strands.
        J Cell Sci. 2002; 115: 2381-2388
        • Barker N.
        • van Es J.H.
        • Kuipers J.
        • et al.
        Identification of stem cells in small intestine and colon by marker gene Lgr5.
        Nature. 2007; 449: 1003-1007
        • Sangiorgi E.
        • Capecchi M.R.
        Bmi1 is expressed in vivo in intestinal stem cells.
        Nat Genet. 2008; 40: 915-920
        • Quante M.
        • Wang T.C.
        Stem cells in gastroenterology and hepatology.
        Nat Rev Gastroenterol Hepatol. 2009; 6: 724-737
        • van der Flier L.G.
        • Clevers H.
        Stem cells, self-renewal, and differentiation in the intestinal epithelium.
        Annu Rev Physiol. 2009; 71: 241-260
        • van der Flier L.G.
        • Haegebarth A.
        • Stange D.E.
        • van de Wetering M.
        • Clevers H.
        OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells.
        Gastroenterology. 2009; 137: 15-17
        • van der Flier L.G.
        • van Gijn M.E.
        • Hatzis P.
        • et al.
        Transcription factor achaete scute-like 2 controls intestinal stem cell fate.
        Cell. 2009; 136: 903-912
        • Sato T.
        • Vries R.G.
        • Snippert H.J.
        • et al.
        Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.
        Nature. 2009; 459: 262-265
        • Barker N.
        • Ridgway R.A.
        • van Es J.H.
        • et al.
        Crypt stem cells as the cells-of-origin of intestinal cancer.
        Nature. 2009; 457: 608-611
        • Verstappen J.
        • Katsaros C.
        • Torensma R.
        • Von den Hoff J.W.
        A functional model for adult stem cells in epithelial tissues.
        Wound Repair Regen. 2009; 17: 296-305
        • Ootani A.
        • Li X.
        • Sangiorgi E.
        • et al.
        Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche.
        Nat Med. 2009; 15: 701-706
        • Watanabe K.
        • Ueno M.
        • Kamiya D.
        • et al.
        A ROCK inhibitor permits survival of dissociated human embryonic stem cells.
        Nat Biotechnol. 2007; 25: 681-686
        • Spradling A.
        • Drummond-Barbosa D.
        • Kai T.
        Stem cells find their niche.
        Nature. 2001; 414: 98-104
        • Li L.
        • Xie T.
        Stem cell niche: structure and function.
        Annu Rev Cell Dev Biol. 2005; 21: 605-631
        • Ohlstein B.
        • Kai T.
        • Decotto E.
        • Spradling A.
        The stem cell niche: theme and variations.
        Curr Opin Cell Biol. 2004; 16: 693-699
        • Xie T.
        • Spradling A.C.
        A niche maintaining germ line stem cells in the Drosophila ovary.
        Science. 2000; 290: 328-330
        • Kosinski C.
        • Li V.S.
        • Chan A.S.
        • 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
        • He X.C.
        • Zhang J.
        • Tong W.G.
        • et al.
        BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.
        Nat Genet. 2004; 36: 1117-1121
        • Mathur D.
        • Bost A.
        • Driver I.
        • Ohlstein B.
        A transient niche regulates the specification of Drosophila intestinal stem cells.
        Science. 2010; 327: 210-213
        • Stappenbeck T.S.
        • Miyoshi H.
        The role of stromal stem cells in tissue regeneration and wound repair.
        Science. 2009; 324: 1666-1669
        • Weaver M.
        • Yingling J.M.
        • Dunn N.R.
        • Bellusci S.
        • Hogan B.L.
        Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development.
        Development. 1999; 126: 4005-4015
        • Haramis A.P.
        • 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
        • Madison B.B.
        • Braunstein K.
        • Kuizon E.
        • Portman K.
        • Qiao X.T.
        • Gumucio D.L.
        Epithelial hedgehog signals pattern the intestinal crypt-villus axis.
        Development. 2005; 132: 279-289
        • Wang Y.
        • Wang L.
        • Iordanov H.
        • et al.
        Epimorphin(-/-) mice have increased intestinal growth, decreased susceptibility to dextran sodium sulfate colitis, and impaired spermatogenesis.
        J Clin Invest. 2006; 116: 1535-1546
        • Shaker A.
        • Swietlicki E.A.
        • Wang L.
        • et al.
        Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion.
        J Clin Invest. 2010; 120: 2081-2093
        • Zacharias W.J.
        • Li X.
        • Madison B.B.
        • et al.
        Hedgehog is an anti-inflammatory epithelial signal for the intestinal lamina propria.
        Gastroenterology. 2010; 138: 2368-2377
        • Tang Y.
        • Swietlicki E.A.
        • Jiang S.
        • et al.
        Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection.
        Am J Physiol Gastrointest Liver Physiol. 2006; 290: G1280-G1288
        • Buhman K.K.
        • Wang L.C.
        • Tang Y.
        • et al.
        Inhibition of Hedgehog signaling protects adult mice from diet-induced weight gain.
        J Nutr. 2004; 134: 2979-2984
        • van den Brink G.R.
        • Bleuming S.A.
        • Hardwick J.C.
        • et al.
        Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation.
        Nat Genet. 2004; 36: 277-282
        • van den Brink G.R.
        • Hardwick J.C.
        Hedgehog Wnteraction in colorectal cancer.
        Gut. 2006; 55: 912-914
        • van Dop W.A.
        • Uhmann A.
        • Wijgerde M.
        • et al.
        Depletion of the colonic epithelial precursor cell compartment upon conditional activation of the Hedgehog pathway.
        Gastroenterology. 2009;
        • Pinto D.
        • Gregorieff A.
        • Begthel H.
        • Clevers H.
        Canonical Wnt signals are essential for homeostasis of the intestinal epithelium.
        Genes Dev. 2003; 17: 1709-1713
        • Kuhnert F.
        • Davis C.R.
        • Wang H.T.
        • et al.
        Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1.
        Proc Natl Acad Sci U S A. 2004; 101: 266-271
        • Ditschkowski M.
        • Einsele H.
        • Schwerdtfeger R.
        • et al.
        Improvement of inflammatory bowel disease after allogeneic stem-cell transplantation.
        Transplantation. 2003; 75: 1745-1747
        • Kreisel W.
        • Potthoff K.
        • Bertz H.
        • et al.
        Complete remission of Crohn's disease after high-dose cyclophosphamide and autologous stem cell transplantation.
        Bone Marrow Transplant. 2003; 32: 337-340
        • Craig R.M.
        • Traynor A.
        • Oyama Y.
        • Burt R.K.
        Hematopoietic stem cell transplantation for severe Crohn's disease.
        Bone Marrow Transplant. 2003; 32: S57-S59
        • Oyama Y.
        • Craig R.M.
        • Traynor A.E.
        • et al.
        Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease.
        Gastroenterology. 2005; 128: 552-563
        • Brittan M.
        • Alison M.R.
        • Schier S.
        • Wright N.A.
        Bone marrow stem cell-mediated regeneration in IBD: where do we go from here?.
        Gastroenterology. 2007; 132: 1171-1173
        • Brittan M.
        • Chance V.
        • Elia G.
        • et al.
        A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts.
        Gastroenterology. 2005; 128: 1984-1995
        • Komori M.
        • Tsuji S.
        • Tsujii M.
        • et al.
        Involvement of bone marrow-derived cells in healing of experimental colitis in rats.
        Wound Repair Regen. 2005; 13: 109-118
        • Khalil P.N.
        • Weiler V.
        • Nelson P.J.
        • et al.
        Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease.
        Gastroenterology. 2007; 132: 944-954
        • Ringden O.
        • Uzunel M.
        • Sundberg B.
        • et al.
        Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon.
        Leukemia. 2007; 21: 2271-2276
        • Le Blanc K.
        • Rasmusson I.
        • Sundberg B.
        • et al.
        Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.
        Lancet. 2004; 363: 1439-1441
        • Gonzalez M.A.
        • Gonzalez-Rey E.
        • Rico L.
        • Buscher D.
        • Delgado M.
        Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses.
        Gastroenterology. 2009; 136: 978-989
        • Semont A.
        • Mouiseddine M.
        • Francois A.
        • et al.
        Mesenchymal stem cells improve small intestinal integrity through regulation of endogenous epithelial cell homeostasis.
        Cell Death Differ. 2010; 17: 952-961
        • Metzger M.
        • Caldwell C.
        • Barlow A.J.
        • Burns A.J.
        • Thapar N.
        Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders.
        Gastroenterology. 2009; 136: 2055-2058