Tales from the crypt: new insights into intestinal stem cells

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The intestinal epithelium withstands continuous mechanical, chemical and biological insults despite its single-layered, simple epithelial structure. The crypt–villus tissue architecture in combination with rapid cell turnover enables the intestine to act both as a barrier and as the primary site of nutrient uptake. Constant tissue replenishment is fuelled by continuously dividing stem cells that reside at the bottom of crypts. These cells are nurtured and protected by specialized epithelial and mesenchymal cells, and together constitute the intestinal stem cell niche. Intestinal stem cells and early progenitor cells compete for limited niche space and, therefore, the ability to retain or regain stemness. Those cells unable to do so differentiate to one of six different mature cell types and move upwards towards the villus, where they are shed into the intestinal lumen after 3–5 days. In this Review, we discuss the signals, cell types and mechanisms that control homeostasis and regeneration in the intestinal epithelium. We investigate how the niche protects and instructs intestinal stem cells, which processes drive differentiation of mature cells and how imbalance in key signalling pathways can cause human disease.

Key points

  • Crypt–villus structure and continuous proliferation enable the intestine to act as an absorptive organ and a protective barrier.

  • Tissue replenishment is fuelled by adult stem cells that divide continuously and reside sequestered away from the intestinal lumen at the bottom of crypts.

  • Stem cells are protected by their niche (Paneth cells and the surrounding mesenchyme) through crypt shape, antimicrobial products, a specialized metabolic environment and neutral competition for limited space.

  • Stemness is a state that is lost when cells leave the stem cell zone, but can also be regained when differentiated cells re-enter the niche.

  • Together with interleukins, Hippo signalling and metabolic cues, WNT, NOTCH, EGF and bone morphogenetic protein signalling regulates stem cell maintenance, regeneration and differentiation.

  • The same signalling cascades involved in stem cell maintenance are key regulators of intestinal differentiation and cooperate to guide cells to one of six mature cell fates.

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Fig. 1: Intestinal structure.
Fig. 2: Main regulatory signals and their sources in the intestinal crypt.
Fig. 3: Main signalling pathways in the intestinal crypt.
Fig. 4: Cell specification in the intestinal epithelium.


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The authors thank J. van Es for critical reading of the manuscript. H.G. was supported by VENI fellowship 016.16.119 of the Netherlands Organisation for Scientific Research NWO.

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Nature Reviews Gastroenterology & Hepatology thanks K. Yan and the other anonymous reviewers(s) for their contribution to the peer review of this work.

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H.G. researched data for the article and wrote the manuscript. H.G. and H.C. contributed equally to discussion of content and reviewing/editing the manuscript before submission.

Correspondence to Hans Clevers.

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Gehart, H., Clevers, H. Tales from the crypt: new insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol 16, 19–34 (2019) doi:10.1038/s41575-018-0081-y

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