Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

STEM CELLS AND RENEWAL IN EPITHELIAL TISSUES
1219
absorptive cell
goblet cell Paneth cell
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
MBoC6 m23.22/22.02
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.
5 µm
enteroendocrine cell
Figure 22–2 The four main differentiated
cell types found in the epithelial lining of
the small intestine. All cells are oriented
with the gut lumen at top. Broad orange
arrows indicate direction of secretion
or uptake of materials for each type of
cell. All of these cells are generated from
undifferentiated multipotent stem cells
living near the bottoms of the crypts (see
Figure 22–1). Absorptive (brush-border)
cells outnumber the other cell types in the
epithelium by about 10:1 or more. The
microvilli on their apical surface provide
a 30-fold increase of surface area, not
only for the import of nutrients but also for
the anchorage of enzymes that perform
the final stages of extracellular digestion,
breaking down small peptides and
disaccharides into monomers that can be
transported across the cell membrane.
Goblet cells secrete mucus; these are
the commonest of the secretory cell
types. Paneth cells secrete (along with
some growth factors) cryptdins—proteins
of the defensin family that kill bacteria.
Different subtypes of enteroendocrine cells
secrete serotonin and peptide hormones
into the gut wall (and thence the blood).
Cholecystokinin is a hormone released
from enteroendocrine cells in response
to the presence of nutrients in the gut. It
binds to receptors on nearby sensory nerve
endings, which relay a signal to the brain
to stop the feeling of hunger once one has
eaten enough. (After T.L. Lentz, Cell Fine
Structure. Philadelphia: Saunders, 1971;
R. Krstić, Illustrated Encyclopedia
of Human Histology. Berlin:
Springer-Verlag, 1984.)
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).