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Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration

Key Points

  • Intestinal stem cells are responsible for the remarkable ability of the intestinal epithelium to efficiently renew and repair itself throughout life.

  • The intestinal stem cells reside within specialized instructive niches at the crypt base. WNT is an essential niche factor supplied by both Paneth cells and non-epithelial cells.

  • The identification of new intestinal stem cell markers has greatly improved our understanding of stem cell biology during homeostasis and disease.

  • Intestinal stem cells can now be purified and used to grow new epithelia ex vivo for regenerative medicine applications.

  • 'Reserve' stem cells are quickly recruited to drive epithelial regeneration following loss of the regular stem cell pool due to injury.

Abstract

Small populations of adult stem cells are responsible for the remarkable ability of the epithelial lining of the intestine to be efficiently renewed and repaired throughout life. The recent discovery of specific markers for these stem cells, together with the development of new technologies to track endogenous stem cell activity in vivo and to exploit their ability to generate new epithelia ex vivo, has greatly improved our understanding of stem cell-driven homeostasis, regeneration and cancer in the intestine. These exciting new insights into the biology of intestinal stem cells have the potential to accelerate the development of stem cell-based therapies and ameliorate cancer treatments.

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Figure 1: Epithelial self-renewal in the intestinal epithelium.
Figure 2: Intestinal stem cells and their defining niche.
Figure 3: Models of epithelial regeneration in the small intestine.

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Acknowledgements

The author thanks the members of the Barker group for critical input. N.B. is supported by the Agency for Science, Technology and Research (A*STAR).

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Correspondence to Nick Barker.

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Glossary

Niches

Specialized instructive microenvironments in which stem cells reside. Niches provide all of the factors necessary to regulate stem cell survival and function.

Intestinal villus

A finger-like structure covered in simple columnar epithelium that projects into the intestinal lumen to maximize the surface area for digestion and absorption.

Duodenum

The proximal third of the small intestine, closest to the stomach. Characterized by the presence of long villi to ensure maximal nutrient digestion and absorption.

Intestinal crypt

Tubular invaginations of the epithelium harbouring the stem cells and their proliferating progeny; responsible for driving epithelial homeostasis and regeneration.

Chimeric mice

Mice that are comprised of two or more populations of genetically distinct cells.

Lgr5–EGFP–ires–CreERT2/R26R–lacZ mouse model

Generated by crossing Lgr5–EGFP–ires–CreERT2 (which encodes a tamoxifen-activatable Cre enzyme that catalyzes recombination across DNA sequences called loxP sites) and R26R (Rosa26 reporter construct)–lacZ mouse strains. Facilitates the conditional activation of the lacZ reporter gene in LGR5-expressing cells in living tissues to evaluate their stem cell identity via lineage tracing.

Bmi1–ires–CreERT2/R26R–lacZ mouse model

Generated by crossing Bmi1-ires-CreERT2 and R26R-lacZ mouse strains. Facilitates the conditional activation of the lacZ reporter gene in BMI1-expressing cells in living tissues to evaluate their stem cell identity via lineage tracing.

Ires

(Internal ribosome entry site). A ribosome-binding site present in the middle of an mRNA that facilitates internal translation initiation to generate an independent protein.

Pulse–chase

A method for detecting quiescent label-retaining cells (LRCs) in vivo. A nucleotide analogue (the label) is administered to the mouse for a short period (the pulse); this is followed by an extended period when no further nucleotide analogue is given (the chase). Actively dividing cells rapidly dilute out the label during DNA replication, and labelled cells are lost within 3–4 rounds of cell division. Non-dividing (quiescent) cells do not dilute out the label and thus remain detectable as LRCs.

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Barker, N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol 15, 19–33 (2014). https://doi.org/10.1038/nrm3721

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  • DOI: https://doi.org/10.1038/nrm3721

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