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

A HIERARCHICAL STEM-CELL SYSTEM: BLOOD CELL FORmation
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Figure 22–33 A developing red blood cell (erythroblast). The cell is shown
extruding its nucleus to become an immature erythrocyte (a reticulocyte),
which then leaves the bone marrow and passes into the bloodstream. The
reticulocyte will lose its mitochondria and ribosomes within a day or two
to become a mature erythrocyte. Erythrocyte clones develop in the bone
marrow on the surface of a macrophage, which phagocytoses and digests
the nuclei discarded by the erythroblasts.
erythroblast
senescent erythrocytes in each of us each day. Young erythrocytes actively protect
themselves from this fate: they have a protein on their surface that binds to an
inhibitory receptor on macrophages and thereby prevents their phagocytosis.
A lack of oxygen or a shortage of erythrocytes stimulates specialized cells in the
kidney to synthesize and secrete increased amounts of erythropoietin into the
bloodstream. The erythropoietin, in turn, boosts the production of erythrocytes.
The effect is rapid: the rate of release of new erythrocytes into the bloodstream
rises steeply 1–2 days after an increase in erythropoietin levels in the bloodstream.
Clearly, the hormone must act on cells that are close precursors of the mature
erythrocytes.
The cells that respond to erythropoietin can be identified by culturing bone
marrow cells in a semisolid matrix in the presence of erythropoietin. In a few
days, colonies of about 60 erythrocytes appear, each founded by a single committed
erythroid progenitor cell. This progenitor depends on erythropoietin for
its survival as well as its proliferation. It does not yet contain hemoglobin, and it
is derived from an earlier type of committed erythroid progenitor whose survival
and proliferation are governed by other factors.
Multiple CSFs Influence Neutrophil and Macrophage Production
The two classes of cells dedicated to phagocytosis, neutrophils and macrophages,
develop from a common progenitor cell called a granulocyte/macrophage (GM)
progenitor cell. Like the other granulocytes (eosinophils and basophils), neutrophils
circulate in the blood for only a few hours before migrating out of capillaries
into the connective tissues or other specific sites, where they survive for only a few
days. They then die by apoptosis and are phagocytosed by macrophages. Macrophages,
in contrast, can persist for months or perhaps even years outside the
bloodstream, where they can be activated by local signals to resume proliferation.
At least seven distinct CSFs that stimulate neutrophil and macrophage colony
formation in culture have been defined, and some or all of these are thought to
act in different combinations to regulate the selective production of these cells
in vivo. These CSFs are synthesized by various cell types—including endothelial
cells, fibroblasts, macrophages, and lymphocytes—and their concentration in
the blood typically increases rapidly in response to bacterial infection in a tissue,
thereby increasing the number of phagocytic cells released from the bone marrow
into the bloodstream.
The CSFs not only operate on the precursor cells to promote the production
of differentiated progeny, they also activate the specialized functions (such as
phagocytosis and target-cell killing) of the terminally differentiated cells. CSFs can
be synthesized artificially and are now widely used in human patients to stimulate
the regeneration of hematopoietic tissue and to boost resistance to infection.
5 µm
MBoC6 m23.44/22.33
reticulocyte
extruded nucleus
will be destroyed
The Behavior of a Hematopoietic Cell Depends Partly on Chance
CSFs are defined as factors that promote the production of colonies of differentiated
blood cells. But precisely what effect does a CSF have on an individual hematopoietic
cell? The factor might control the rate of cell division or the number of
division cycles that the progenitor cell undergoes before differentiating; it might
act late in the hematopoietic lineage to facilitate differentiation; it might act early
to influence commitment; or it might simply increase the probability of cell survival
(Figure 22–34). By monitoring the fate of isolated individual hematopoietic
cells in culture, it has been possible to show that a single CSF, such as granulocyte/