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

1222 Chapter 22: Stem Cells and Tissue Renewal
1 day 5 days 60 days Figure 22–6 Lgr5-expressing stem cells
and their progeny in the small intestine.
The method shown in Figure 22–5 was
used here to mark single intestinal stem
cells and trace the fates of their progeny.
The Lgr5 gene encodes a member of the
family of G-protein-linked transmembrane
receptors, and it is expressed specifically
in stem cells near the crypt base. Because
the Lgr5 promoter was used to drive
expression of CreERT2, treatment with
a low dose of tamoxifen resulted in
occasional stem cells expressing LacZ.
These cells and all of their progeny could
subsequently be detected with a blue
histochemical stain. All of the blue cells in
these images derive from a single Lgr5-
expressing stem cell. After 60 days, the
blue progeny of this cell are seen to extend
The Two Daughters of a Stem Cell Do Not Always Have to
Become Different
If the number of stem cells in a crypt is to remain stable, each stem-cell division
must on average generate one daughter that remains a stem cell and one that
becomes committed to differentiation. In principle, this could be achieved in at
least two ways (Figure 22–7).
MBoC6 n22.102/22.06
One mechanism—the simplest at first sight—would be through asymmetric
division: processes internal to the dividing stem cell could distribute regulatory
factors asymmetrically to its two daughters, as occurs in Drosophila neuroblast
divisions (see Figure 21–36). The factors inherited by one daughter would cause it
to remain a stem cell, while those inherited by the other would drive it toward differentiation.
This strategy would guarantee that the original stem cell would give
rise to precisely one stem cell in every subsequent cell generation.
An alternative strategy would be based on a choice that each daughter makes
independently of its sister: in normal circumstances, each would have a 50% probability
of remaining as a stem cell and a 50% probability of commitment to differentiation.
Sometimes the two daughters of a stem cell would thus have opposite
fates, sometimes the same. The choice that each cell makes might either be stochastic,
like the flip of a coin, or governed by the environment in which the cell
finds itself. A strategy of independent choices is more flexible than that of strict
asymmetric division. In particular, environmental factors can control the balance
of probabilities, adjusting them in favor of the stem-cell option where more stem
cells are needed, as they often are, either for growth or for damage repair.
Clonal analysis gives a way to distinguish between the two strategies, since
they give quite different predictions as to the expected number of clones of different
sizes produced from individual stem cells (see Figure 22–7). For the gut, the
findings seem clear: the independent-choice theory fits the observations, and the
asymmetric-division theory does not.
Paneth Cells Create the Stem-Cell Niche
100 µm
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
all the way up a villus. These progeny
can be shown to include all types of
differentiated cells, as well as persistent
Lgr5-expressing cells at the crypt base.
This proves that Lgr5-expressing cells are
multipotent stem cells. (From N. Barker et
al., Nature 449:1003–1007, 2007. With
permission from Macmillan Publishers Ltd.)