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Organizing cell renewal in the intestine: stem cells, signals and combinatorial control

Nature Reviews Genetics volume 7, pages 349–359 (2006)Cite this article

Key Points

  • The epithelial lining of the intestine renews itself more rapidly than any other tissue in the vertebrate body, replacing the entire population of differentiated cells that cover the intestinal villi every few days.

  • Stem cells and their transit-amplifying progeny reside in intervillus pockets (in the fetus or neonate) or crypts of Lieberkühn (in the adult), and give rise to four classes of non-dividing differentiated cells — three secretory and one absorptive.

  • Transit-amplifying cells in the crypts probably become committed as secretory or absorptive progenitors several cycles before they stop dividing. The secretory progenitors express mouse atonal homologue 1 (Math1), and no secretory cells are produced when Math1 is defective.

  • Epithelial cells in each stem-cell region (crypt or pocket) produce a hedgehog signal that acts on the mesenchyme, evoking expression of bone morphogenetic protein (BMP). BMP acts back on the epithelium to inhibit formation of ectopic stem-cell regions.

  • The stem-cell regions of epithelium maintain themselves by canonical Wnt signalling, apparently through an auto-activating feedback loop.

  • When the canonical Wnt signalling pathway is blocked, proliferation fails and secretory cells are lacking; when the pathway is overactivated, proliferation is excessive and tumours develop, containing a mixture of cell types (adenomatous polyps).

  • The proliferative epithelial cells in the crypts also interact with one another by Notch signalling, mediating lateral inhibition. When the Notch signalling pathway is blocked, proliferation fails and all the crypt cells become secretory; when the pathway is overactivated, proliferation continues but no secretory cells are produced.

  • Wnt and Notch signals collaborate to maintain intestinal stem cells: neither pathway on its own is sufficient. But Wnt pathway activation can induce expression of Notch pathway components and so produce the collaborative effect.

  • Wnt signalling also regulates the expression of Eph/ephrins. Eph/ephrin signalling in turn controls the migratory behaviour that keeps proliferative and differentiated cells segregated along the crypt–villus axis.

  • Wnt and Notch signals collaborate in a remarkably similar way to maintain stem cells in the haemopoietic system and the CNS. But in some other tissues where both pathways are crucial, such as the epidermis, the rules of stem-cell maintenance are different.

Abstract

The lining of the intestine is renewed at an extraordinary rate, outpacing all other tissues in the vertebrate body. The renewal process is neatly organized in space, so that the whole production line, from the ever-youthful stem cells to their dying, terminally differentiated progeny, is laid out to view in histological sections. A flurry of recent papers has clarified the key regulatory signals and brought us to the point where we can begin to give a coherent account, for at least one tissue, of how these signals collaborate to organize the architecture and behaviour of a stem-cell system.

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Figure 1: The distribution of epithelial cell types in the mammalian small intestine.
Figure 2: Morphogenesis of the small intestine in the mouse.
Figure 3: Signalling pathways in the small intestine.
Figure 4: Wnt and Notch signalling cooperate to maintain stem cells.

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Acknowledgements

We thank N. Wright and the anonymous referees for helpful comments, and Cancer Research UK for financial support.

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  1. Vertebrate Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Cécile Crosnier, Despina Stamataki & Julian Lewis

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DATABASES

OMIM

juvenile polyposis syndrome

Glossary

Niche

The specific microenvironment that stem cells inhabit.

Clonal analysis

Analysis of the composition and distribution of the clones of cells that are descended from individual, heritably marked cells, in order to discover the fate of these progenitors.

Pseudostratified

Describes an epithelium that, because of the uneven positions of the cell nuclei, seems to contain several layers of cells (stratified) but is in fact composed of a single one, in which all cells make contact with the basal surface.

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Crosnier, C., Stamataki, D. & Lewis, J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nat Rev Genet 7, 349–359 (2006). https://doi.org/10.1038/nrg1840

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