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

1244 Chapter 22: Stem Cells and Tissue Renewal
The stepwise nature of commitment means that the hematopoietic system can
be viewed as a hierarchical family tree of cells. Multipotent stem cells give rise
to committed progenitor cells, which are specified to give rise to only one or a
few blood cell types. The committed progenitors divide rapidly, but only a limited
number of times, before they terminally differentiate into cells that divide no further
and die after several days or weeks. Figure 22–31 depicts the hematopoietic
family tree. It should be noted, however, that variations are thought to occur: not
all stem cells generate the identical patterns of progeny via precisely the same
sequence of steps.
Stem Cells Depend on Contact Signals From Stromal Cells
Like the stem cells of other tissues, hematopoietic stem cells depend on signals
from their niche, in this case created by the specialized connective tissue of the
bone marrow. (This is the site in adult humans; during development, and in nonhuman
mammals such as the mouse, hematopoietic stem cells can also make
their home in other tissues—notably liver and spleen.) When they lose contact
with their niche, the hematopoietic stem cells tend to lose their stem-cell potential
(Figure 22–32). Evidently the loss of potency is not absolute or instantaneous,
however, since the stem cells can still survive journeys via the bloodstream to colonize
other sites in the body.
Factors That Regulate Hematopoiesis Can Be Analyzed in Culture
While the stem cells depend on contact with bone marrow stromal cells for longterm
maintenance, their committed progeny do not, or at least not to the same
degree. These cells can thus be dispersed and cultured in a semisolid matrix of
dilute agar or methylcellulose, and factors derived from other cells can be added
artificially to the medium. The semisolid matrix inhibits migration, so that the
progeny of each isolated precursor cell remain together as an easily distinguishable
colony. A single committed neutrophil progenitor, for example, may give rise
to a clone of thousands of neutrophils. Such culture systems have provided a way
to assay for the factors that support hematopoiesis and hence to purify them and
explore their actions. These substances are glycoproteins and are usually called
colony-stimulating factors (CSFs). Some of these factors circulate in the blood
and act as hormones, while others act in the bone marrow as secreted local mediators;
still others take the form of membrane-bound signals that act through cell–
cell contact.
An important example of the latter is a protein called Steel or Stem Cell Factor
(SCF ). This is expressed both in the bone marrow stroma (where it helps to
define the stem-cell niche) and along pathways of migration, and it occurs both
in a membrane-bound and a soluble form. It binds to a receptor tyrosine kinase
called Kit, and it is required during development for guidance and survival not
only of hematopoietic cells but also of other migratory cell types—specifically,
germ cells and pigment cells.
Kit
Kit
ligand
(SCF)
stem cell
transit
amplifying
cell
COMMIT TO
DIFFERENTIATION
OR DIE
STEM CELL DIVIDES
other
receptorligand
pairs
stromal
cell
stem cell
STEM CELL
MAINTAINED
stromal
cell
Figure 22–32 Dependence of
hematopoietic stem cells on contact
with stromal cells. The contact-dependent
interaction between the Kit receptor
and its MBoC6 ligand m23.43/22.32
is one of several signaling
mechanisms thought to be involved in
hematopoietic stem-cell maintenance.
The real system is certainly more
complex. Moreover, the dependence of
hematopoietic cells on contact with stromal
cells cannot be absolute, since small
numbers of the functional stem cells can be
found free in the circulation. SCF, stem-cell
factor.
Erythropoiesis Depends on the Hormone Erythropoietin
The best understood of the CSFs that act as hormones is the glycoprotein erythropoietin,
which is produced in the kidneys and regulates erythropoiesis, the formation
of red blood cells, to which we now turn.
The erythrocyte is by far the most common type of cell in the blood (see Table
22–1). When mature, it is packed full of hemoglobin and contains hardly any of
the usual cell organelles. In an erythrocyte of an adult mammal, even the nucleus,
endoplasmic reticulum, mitochondria, and ribosomes are absent, having been
extruded from the cell in the course of its development (Figure 22–33). The erythrocyte
therefore cannot grow or divide, and it has a limited life-span—about 120
days in humans or 55 days in mice. Worn-out erythrocytes are phagocytosed and
digested by macrophages in the liver and spleen, which remove more than 10 11