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)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Small intestine: anatomy and structural anomalies.in: Yamada T. Textbook of gastroenterology. Wiley-Blackwell, Chichester, West Sussex, UK2009: 1085-1107
- The intestinal stem cell niche: there grows the neighborhood.Proc Natl Acad Sci U S A. 2001; 98: 12334-12336
- Live and let die in the intestinal epithelium.Curr Opin Cell Biol. 2003; 15: 763-770
- Intestinal epithelial stem cells and progenitors.Methods Enzymol. 2006; 419: 337-383
- Growth of intestinal epithelium in organ culture is dependent on EGF signalling.Exp Cell Res. 2005; 303: 252-262
- Coexistence of quiescent and active adult stem cells in mammals.Science. 2010; 327: 542-545
- Current view: intestinal stem cells and signaling.Gastroenterology. 2008; 134: 849-864
- 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
- Wnt signaling, lgr5, and stem cells in the intestine and skin.Am J Pathol. 2009; 174: 715-721
- 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
- The intestinal epithelial stem cell: the mucosal governor.Int J Exp Pathol. 1997; 78: 219-243
- A new identity for the elusive intestinal stem cell.Nat Genet. 2008; 40: 818-819
- Intestinal stem cells protect their genome by selective segregation of template DNA strands.J Cell Sci. 2002; 115: 2381-2388
- Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature. 2007; 449: 1003-1007
- Bmi1 is expressed in vivo in intestinal stem cells.Nat Genet. 2008; 40: 915-920
- Stem cells in gastroenterology and hepatology.Nat Rev Gastroenterol Hepatol. 2009; 6: 724-737
- Stem cells, self-renewal, and differentiation in the intestinal epithelium.Annu Rev Physiol. 2009; 71: 241-260
- OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells.Gastroenterology. 2009; 137: 15-17
- Transcription factor achaete scute-like 2 controls intestinal stem cell fate.Cell. 2009; 136: 903-912
- Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.Nature. 2009; 459: 262-265
- Crypt stem cells as the cells-of-origin of intestinal cancer.Nature. 2009; 457: 608-611
- A functional model for adult stem cells in epithelial tissues.Wound Repair Regen. 2009; 17: 296-305
- Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche.Nat Med. 2009; 15: 701-706
- A ROCK inhibitor permits survival of dissociated human embryonic stem cells.Nat Biotechnol. 2007; 25: 681-686
- Stem cells find their niche.Nature. 2001; 414: 98-104
- Stem cell niche: structure and function.Annu Rev Cell Dev Biol. 2005; 21: 605-631
- The stem cell niche: theme and variations.Curr Opin Cell Biol. 2004; 16: 693-699
- A niche maintaining germ line stem cells in the Drosophila ovary.Science. 2000; 290: 328-330
- 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
- BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.Nat Genet. 2004; 36: 1117-1121
- A transient niche regulates the specification of Drosophila intestinal stem cells.Science. 2010; 327: 210-213
- The role of stromal stem cells in tissue regeneration and wound repair.Science. 2009; 324: 1666-1669
- Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development.Development. 1999; 126: 4005-4015
- De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine.Science. 2004; 303: 1684-1686
- Epithelial hedgehog signals pattern the intestinal crypt-villus axis.Development. 2005; 132: 279-289
- Epimorphin(-/-) mice have increased intestinal growth, decreased susceptibility to dextran sodium sulfate colitis, and impaired spermatogenesis.J Clin Invest. 2006; 116: 1535-1546
- Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion.J Clin Invest. 2010; 120: 2081-2093
- Hedgehog is an anti-inflammatory epithelial signal for the intestinal lamina propria.Gastroenterology. 2010; 138: 2368-2377
- 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
- Inhibition of Hedgehog signaling protects adult mice from diet-induced weight gain.J Nutr. 2004; 134: 2979-2984
- Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation.Nat Genet. 2004; 36: 277-282
- Hedgehog Wnteraction in colorectal cancer.Gut. 2006; 55: 912-914
- Depletion of the colonic epithelial precursor cell compartment upon conditional activation of the Hedgehog pathway.Gastroenterology. 2009;
- Canonical Wnt signals are essential for homeostasis of the intestinal epithelium.Genes Dev. 2003; 17: 1709-1713
- 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
- Improvement of inflammatory bowel disease after allogeneic stem-cell transplantation.Transplantation. 2003; 75: 1745-1747
- Complete remission of Crohn's disease after high-dose cyclophosphamide and autologous stem cell transplantation.Bone Marrow Transplant. 2003; 32: 337-340
- Hematopoietic stem cell transplantation for severe Crohn's disease.Bone Marrow Transplant. 2003; 32: S57-S59
- Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease.Gastroenterology. 2005; 128: 552-563
- Bone marrow stem cell-mediated regeneration in IBD: where do we go from here?.Gastroenterology. 2007; 132: 1171-1173
- A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts.Gastroenterology. 2005; 128: 1984-1995
- Involvement of bone marrow-derived cells in healing of experimental colitis in rats.Wound Repair Regen. 2005; 13: 109-118
- Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease.Gastroenterology. 2007; 132: 944-954
- Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon.Leukemia. 2007; 21: 2271-2276
- Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.Lancet. 2004; 363: 1439-1441
- Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses.Gastroenterology. 2009; 136: 978-989
- Mesenchymal stem cells improve small intestinal integrity through regulation of endogenous epithelial cell homeostasis.Cell Death Differ. 2010; 17: 952-961
- Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders.Gastroenterology. 2009; 136: 2055-2058
Article info
Publication history
Published online: July 05, 2010
Accepted:
June 10,
2010
Received in revised form:
June 9,
2010
Received:
May 17,
2010
Footnotes
Supported by N1HDK61216, DK46122 (DR) and A6AFFTA (AS).
Identification
Copyright
© 2010 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
