As if on a conveyor belt, the absorptive, goblet, and enteroendocrine cells travel mainly upward from their site of birth in the crypt, by a sliding movement in the plane of the epithelial sheet, to cover the surfaces of the villi. Within 3–5 days (in the mouse) after emerging from the crypts, the cells reach the tips of the villi, where they undergo apoptosis and are finally discarded into the gut lumen (see
Figure 22–1 Renewal of the gut lining.
(a) the pattern of cell turnover and proliferation in the epithelium that forms the lining of the small intestine. Stem cells (red) lie at the crypt base, interspersed among nondividing differentiated cells (paneth cells). progeny of the stem cells move mainly upward from the crypts onto the villi; after a few quick divisions, they cease dividing and differentiate—some of them while still in the crypt, most of them as they emerge from the crypt. the paneth cells, like the other nondividing differentiated cells, are continually replaced by progeny of the stem cells, but they migrate downward to the crypt base and survive there for many weeks. (b) photograph of a section of part of the lining of the small intestine, showing the crypts and villi. note the mixture of differentiated cell types, all generated from the stem cells; these are primarily absorptive cells, with mucus-secreting goblet cells (stained red) interspersed among them. enteroendocrine cells (not labeled) are less numerous and less easy to identify without special stains.
Movie 20.6). The Paneth cells in the crypts are produced in much smaller numbers and have a different migration pattern. They live at the bottom of the crypts, where they too are continually replaced, although not so rapidly, persisting for several weeks (in the mouse) before undergoing apoptosis and being phagocytosed by their neighbors.
The central problem is to understand the processes in the crypt that generate a continual supply of all these nondividing, terminally differentiated cell types.
Stem Cells of the Small intestine lie at or near the base of each Crypt
The general pattern of cell proliferation and migration in the gut lining is revealed by a simple labeling method that uses injected pulses of tritiated (radioactive) thymidine or of a thymidine analog that can be detected in tissue sections. Cells that are in S phase of the division cycle incorporate the marker molecule into their DNA, and their fate can then be followed over subsequent hours and days. If a cell divides after incorporation of the label, the label becomes diluted, halving with each cell cycle. This can be quantified. Experiments based on this labeling method confirm, first of all, that dividing cells are confined to the crypts and that the differentiated cell types listed above do not divide. Second, the most rapidly dividing cells, with a cycle time of about 12 hours in the mouse, are shown to lie in the middle and upper parts of the crypt, and these cells are all fated to differentiate and stop dividing (see Figure 22–1A). Just above the base of the crypt, interspersed among the Paneth cells, lie cells that divide more slowly. These are the stem cells, which feed some of their progeny into the higher levels of the crypt destined for differentiation, while other progeny remain at the crypt base to continue the whole process. The rapidly dividing cells above these stem cells are derived from them, but already committed to differentiation. These cells are called committed precursors or transit amplifying cells, since their divisions serve to amplify the number of differentiated cells that ultimately result from each stem-cell division.
the two daughters of a Stem Cell Face a Choice
Stem cells have a critical role in a variety of tissues, and it is useful to list their defining properties: 1.
A stem cell is not itself terminally differentiated: that is, it is not at the end of a pathway of differentiation.
2.
It can divide without limit (or at least for the lifetime of the animal).
3.
When it divides, each daughter has a choice: it can either remain a stem cell, or it can embark on a course that commits it to terminal differentiation (Figure 22–3).