Further Development 5.7: Regulatory Mechanisms in the Crypt

Stem Cells: Their Potential and Their Niches

With nearly 80% of the intestinal stem cell’s surface in direct contact with the Paneth cell, the Paneth cell is a vital contributor to stem cell regulation. Each niche contains about 15 Paneth cells and an equal number of CBCCs. Deleting the Paneth cells destroys the ability of the stem cells to generate other cells. Paneth cells express several paracrine and juxtacrine factors, including, but not limited to, Wnt3a and Delta-like-4 (Dll4), an activator of Notch (Sato et al. 2009; Barker 2014; Krausova and Korinek 2014). When Dll4 binds to Notch re-ceptors on the intestinal stem cells, it is interpreted as a signal for sustained proliferation and lineage specifi-cation toward a secretory rather than an absorptive cell fate (see Figure 5.14C; Fre et al. 2011; Pellegrinet et al. 2011).

The stromal cells below the crypt epithelium also regulate the intestinal stem cell niche by secreting Wnt2b, which creates an opposing gradient to the Bmp4 that is expressed more toward the luminal surface (from the top of the crypt) (see Figure 5.14C). CBCCs express both the Frizzled7 and BMPR1a receptors for Wnt2b and Bmp4, respectively (He et al. 2004; Farin et al. 2012; Flanagan et al. 2015). The current model is that Wnt signaling promotes survival and proliferation of the CBCCs and progenitor cells, whereas the opposing BMP signals promote progressive differentiation within the crypt in the direction of the villus (Carulli et al. 2014; Krausova and Korinek 2014).

There exists another small population of intestinal stem cells called the “+4 cells” due to their location next to the fourth Paneth cell from the base of the crypt (see Figure 5.14C; Potten et al. 1978; Potten et al. 2002; Clevers 2013). Like CBCCs, +4 cells can generate all the cell types of the intestine. Some reports indicate that +4 cells divide at a slower rate than CBCCs, which suggests that they may be the quiescent stem cell of the crypt. It is at least indisputable that the +4 cells make important contributions to intestinal homeostasis; sig-nificant debate still surrounds the notion that they represent the niche’s quiescent stem cell, however (Carulli et al. 2014).

Literature Cited

Barker, N. 2014. Adult intestinal stem cells: Critical drivers of epithelial homeostasis and regenera-tion. Nat. Rev. Mol. Cell Biol. 15: 19–33.
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Carulli, A. J., L. C. Samuelson and S. Schnell. 2014. Unraveling intestinal stem cell behavior with models of crypt dynamics. Integr. Biol. (Camb.) 6: 243–257.
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Clevers, H. 2013. Stem cells: A unifying theory for the crypt. Nature 495: 53–54.
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Clevers, H. 2013. The intestinal crypt, a prototype stem cell compartment. Cell 154: 274–284.
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Farin, H. F., J. H. Van Es and H. Clevers. 2012. Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells. Gastroenterology 143: 1518–1529.
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Flanagan, D. J and 15 others. 2015. Frizzled7 functions as a Wnt receptor in intestinal epithelial Lgr5+ stem cells. Stem Cell Reports 4: 759–767.
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Fre, S. and 9 others. 2011. Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice. PLoS One 6: e25785.
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He, X. C. and 11 others. 2004. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-b-catenin signaling. Nat. Genet. 36: 1117–1121.
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Krausova, M. and V. Korinek. 2014. Wnt signaling in adult intestinal stem cells and cancer. Cell Signal. 26: 570–579.
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Pellegrinet, L. and 9 others. 2011. Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140: 1230–1240.e1–7.
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Potten, C. S., G. Owen and D. Booth. 2002. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J. Cell Sci. 115: 2381–2388.
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Potten, C. S., W. J. Hume, P. Reid and J. Cairns. 1978. The segregation of DNA in epithelial stem cells. Cell 15: 899–906.
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Sato, T. and 10 others. 2009. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesen-chymal niche. Nature 459: 262–265.

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