There are about 15 Lgr5-expressing stem cells in each crypt. They are slim and columnar, and they sit at the crypt base interspersed among the Paneth cells (see Figure 22–6). This is the intestinal stem-cell niche: the Paneth cells generate signals, including a strong Wnt signal, that act over a short range to maintain the stem-cell state. Signal proteins from the connective tissue surrounding the crypt base help to reinforce the localizing signal from the Paneth cells; Lgr5 itself is a receptor for one of these proteins, called R-spondin.
In the intestine, it seems that the niche created by the Paneth cells has space for only a limited number of stem cells, and when these divide, it is a random
POSSIBLE OUTCOMES after frst division cycle of stem cell after frst division cycle of stem cell terminally differentiated cell after second division cycle of stem cell after second division cycle of stem cell POSSIBLE OUTCOMES etc. etc. terminally differentiated cell environmental factors help determine cell fate or or or or or or or or choice determined by asymmetry in dividing stem cell choice determined stochastically and/or by environment localizeddeterminant
Figure 22–7 Two ways for a stem cell to produce daughters with different fates: asymmetric division and independent choice. (a) the asymmetric-division strategy gives a clone consisting of precisely one stem cell plus a steadily increasing number of differentiating cells, in proportion to the number of cell divisions. (b) the independent-choice strategy is more variable in its outcome. with a choice made at random by each daughter and with a 50% probability for each one to remain a stem cell or differentiate, there is, for example, a 25% chance at the first division that both daughters will differentiate, so that the clone eventually goes extinct. or, at this division or later, a preponderance of daughters may chance to retain stem-cell character, creating a clone that persists and increases in size. with the help of some mathematics, the probability distribution of clone sizes generated from a single stem cell at any given time can be predicted on this stochastic assumption. the observations in the gut and elsewhere fit the stochastic independent-choice strategy, but not the asymmetric-division strategy.
matter which of them are pushed out of the nest and condemned to differentiation and which stay in place as stem cells for the future. In most other stem-cell systems where the question has been examined, it appears that the fates of the daughters of a stem cell are assigned in a similar way, independently and subject to influence from the cells’ environment.
The Paneth cells themselves are progeny of the stem cells, suggesting that the intestinal stem-cell system is in some way self-maintaining and self-organizing. This is demonstrated in a striking way by taking single dissociated Lgr5-expressing cells and allowing them to proliferate in culture, embedded in a cell-free matrix rich in the basal-lamina component laminin (mimicking basal lamina). The cells proliferate, forming at first small, round epithelial vesicles. Within a few days, however, one or another of the cells in the vesicle, at random, begins to differentiate as a Paneth cell. This induces its neighbors to behave as stem cells and initiates transformation of the simple vesicle into an organized structure, or organoid (Figure 22–8A,B). Protrusions resembling crypts grow out into the surrounding matrix and contain Paneth cells, Lgr5-expressing stem cells, and the transit amplifying cells derived from them; these cell types are confined to the cryptlike structures. Terminally differentiated, nondividing absorptive cells line the other parts of the organoid epithelium, with their microvilli facing the lumen. Goblet and enteroendocrine cells are also present, scattered through the epithelium, and the whole “minigut” structure, with all its cell types, grows and renews itself in much the same way as the lining of the normal intestine.