Figure 22–8 Genesis of a minigut from a single Lgr5-expressing cell cultured in a cell-free matrix. (a,b) the founder cell first divides to form a small vesicle. at random, one or more of the cells in this vesicle differentiates as a paneth cell (blue). this cell maintains Lgr5 expression (yellow) in its immediate neighbors, which persist as stem cells that generate the full range of intestinal cell types. (C ) Schematic diagram of the key organizing signals. the paneth cells organize crypts by producing a wnt signal that acts on neighboring cells and keeps them proliferating in the stem-cell state. a repulsive interaction based on ephrin–eph binding causes the crypt cell types (which express ephb, induced by wnt) to segregate from the nondividing differentiated villus cell types (which express ephrinb). both ephrin and eph are cell-surface proteins attached to the plasma membrane; in many tissues, two cells that contain a different member of this pair repel each other when they touch (see Figure 21–49). (adapted from t. Sato and h. Clevers, Science 340:1190– 1194, 2013. with permission from aaaS.) ephrin–eph Signaling drives Segregation of the different Gut Cell types
The remarkable self-organizing behavior of the cultured organoids suggests that some interaction among the different epithelial cells drives them to segregate from one another. The ephrin–Eph signaling pathway (discussed in Chapter 15) appears to be responsible. The cells that live in the crypts express EphB receptor proteins, while absorptive, goblet, and enteroendocrine cells, as they begin to differentiate, switch off expression of this receptor and instead switch on expression of its ligands, cell-surface proteins of the EphrinB family (Figure 22–8C). In various other tissues, cells expressing Eph proteins are repelled by contacts with cells expressing ephrins on their surface (see Figures 21–49 and 21–79). It seems that the same is true in the gut lining, and that this mechanism serves to keep the cells segregated and in their proper places. In EphB knockout mutants, the populations become mixed, so that, for example, Paneth cells wander out onto the villi.
notch Signaling Controls Gut Cell diversification and helps maintain the Stem-Cell State
If a single type of stem cell generates all the differentiated cell types in the gut lining, what causes the progeny of this stem cell to diversify? Notch signaling has this role in many other systems, where it mediates lateral inhibition—a competitive interaction that drives neighboring cells toward different fates (see Figure 15–58 and Figure 21–35). All the essential components of the Notch pathway are expressed in the crypts; it seems that Wnt signaling maintains them there. If Notch signaling is abruptly blocked, within a few days all the cells in the crypts differentiate as goblet cells, and absorptive cells cease to be produced; conversely, if Notch signaling is artificially activated in all the cells, absorptive cells continue
IN CRYPT, to be generated but no goblet cells are produced. This reflects the lateral inhibition mechanism operating in normal animals: the nascent goblet (and other secretory) cells express the Notch ligand Delta and thereby activate Notch in their neighbors, inhibiting them from differentiating as secretory (Figure 22–9).
Delta-Notch signaling is crucial not only in the transit amplifying population, but also at the crypt base: the Paneth cells express Delta and this activates Notch in the stem cells, inhibiting differentiation. Without this influence, the stem cells lose their special character and differentiate as secretory cells. Thus maintenance of the intestinal stem-cell state requires a combination of signals, with both Wnt and Notch acting as central players.
the epidermal Stem-Cell System maintains a Self-Renewing waterproof barrier