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

1242 Chapter 22: Stem Cells and Tissue Renewal
megakaryocyte process
budding off platelets endothelial cell of sinus wall
lumen of blood sinus
red blood cell
Figure 22–29 A megakaryocyte among
other developing blood cells in the bone
marrow. The megakaryocyte’s enormous
size results from its having a highly
polyploid nucleus. One megakaryocyte
produces about 10,000 platelets, which
split off from long processes that extend
through holes in the walls of an adjacent
blood sinus.
developing
blood cells
megakaryocyte
bone
marrow
20 µm
Bone Marrow Contains Multipotent Hematopoietic Stem Cells,
Able to Give Rise to All Classes of Blood Cells
In the bone marrow, the developing blood cells and their precursors, including
the stem cells, are intermingled with one another, as well as with fat cells and
other stromal cells (connective-tissue cells), which produce a delicate supporting
meshwork of collagen fibers and other extracellular matrix components. In
addition, the whole tissue is richly supplied with thin-walled blood vessels, called
blood sinuses, into which the new blood cells are discharged. Megakaryocytes are
also present; these, unlike other blood cells, remain in the bone marrow when
mature and are one of its most striking features, being extraordinarily large (diameter
up to 60 μm) with a highly MBoC6 polyploid m23.40/22.29 nucleus. They normally lie close beside
blood sinuses, and they extend processes through holes in the endothelial lining
of these vessels; platelets pinch off from the processes and are swept away into the
blood (Figure 22–29 and Movie 22.4).
Because of the complex arrangement of the cells in bone marrow, it is difficult
to identify in ordinary tissue sections any but the immediate precursors of the
mature blood cells. There is no obvious visible characteristic by which we can recognize
the ultimate stem cells. In the case of hematopoiesis, the stem cells were
first identified by a functional assay that exploited the wandering lifestyle of blood
cells and their precursors.
When an animal is exposed to a large dose of x-rays, most of the hematopoietic
cells are destroyed and the animal dies within a few days as a result of its inability
to manufacture new blood cells. The animal can be saved, however, by a transfusion
of cells taken from the bone marrow of a healthy, immunologically compatible
donor. Among these cells there are some that can colonize the irradiated
host and permanently reequip it with hematopoietic tissue (Figure 22–30). Such
experiments prove that the marrow contains hematopoietic stem cells. They also
show how we can assay for the presence of hematopoietic stem cells and hence
discover the molecular features that distinguish them from other cells.
For this purpose, cells taken from bone marrow are sorted (using a fluorescence-activated
cell sorter) according to the surface antigens that they display,
and the different fractions are transfused back into irradiated mice. If a fraction
rescues an irradiated host mouse, it must contain hematopoietic stem cells. In this
way, it has been possible to show that the hematopoietic stem cells are characterized
by a specific combination of cell-surface proteins, and by appropriate sorting
we can obtain virtually pure stem-cell preparations. The stem cells turn out to be a
tiny fraction of the bone marrow population—about 1 cell in 50,000–100,000; but
this is enough. A single such cell injected into a host mouse with defective hematopoiesis
is sufficient to reconstitute its entire hematopoietic system, generating a
complete set of blood cell types, as well as fresh stem cells. This and other experiments
(using artificial lineage markers) show that the individual hematopoietic
stem cell is multipotent and can give rise to the complete range of blood cell types,
both myeloid and lymphoid, as well as to new stem cells like itself (Figure 22–31).
x-irradiation halts blood cell
production; mouse would die
if no further treatment were given
INJECT BONE MARROW CELLS
FROM HEALTHY DONOR
mouse survives; the injected stem
cells colonize its hematopoietic tissues
and generate a steady supply of
new blood cells
Figure 22–30 Rescue of an irradiated
mouse by a transfusion of bone marrow
cells. An essentially similar procedure is
used in the treatment of leukemia in human
patients by bone marrow transplantation.