Cancer Stem Cells
227
elements, for example, red blood cells,
platelets, granulocytes, macrophages, and
B- and T-lymphocytes. These cells are re-
sponsible for oxygenation, prevention of
bleeding, infection prevention, and im-
munity, respectively. The HSC pool has
three fundamental properties in the adult.
First, self-renewal allows the maintenance
of the stem cell pool. Self-renewal is not
analagous to proliferation; self-renewal is
a cell division in which one or both
the daughter cells remain undifferenti-
ated and retain the ability to give rise
to another stem cell as well as to differ-
entiated progeny. Proliferation does not
require either daughter cell to be a stem
cell, nor does it retain the ability to give rise
to multiple lineages. Second, they must
differentiate in order to maintain a ge-
netically regulated pool of mature cells
under homeostatis, and to produce in-
creased numbers of a particular lineage
in response to environmental stresses, in-
cluding bleeding or infection. Third, the
total number of HSCs must be under
strict genetic regulation. Since only stem
cells comprise a rare subset of cells within
a tissue, they must be isolated in or-
der to study their biological, molecular,
and biochemical properties. Although it is
thought that they give rise to most tissues,
stem cells have been rigorously identi±ed
and puri±ed only from a handful. The
stem cells that give rise to the lympho-
hematopoietic system, called
hematopoietic
stem cells
,we
reoneo
fthe±
rs
ts
temce
l
l
populations characterized and have been
isolated from both mice and humans. The
utility of stem cell biology in the clinic
has already been demonstrated in can-
cer therapy with their extensive use for
bone marrow transplantation to regener-
ate the hematolymphoid system following
myeloablative protocols.
3.2
The Hierarchy of the Hematopoietic System
The multipotent cells of the hematopoietic
system constitute only 0.05% of mouse
bone marrow cells and are heterogeneous
in their ability to self-renew. The lym-
phohematopoietic system consists of a
hierarchy in which long-term HSCs give
rise to short-term HSCs, which in turn give
rise to multipotent progenitors; only long-
term and short-term HSCs have detectable
self-renewal potential. Cells become more
mitotically active as they progress through
the differentiation hierarchy, but lose the
ability to self-renew. Only long-term HSCs
can replenish the full hematopoietic sys-
tem for the lifetime of an animal; short-
term HSCs and multipotent progenitors
reconstitute lethally irradiated mice for less
than eight weeks.
3.3
Self-renewal: The DeFning Property of Stem
Cells
While
the
functional
and
phenotypic
properties of mouse and human HSCs
have been extensively studied, our un-
derstanding of the fundamental prop-
erty de±ning stem cells, self-renewal, is
minimal. HSCs differentiate when ex-
posed to combinations of growth fac-
tors that can induce extensive prolif-
e
r
a
t
i
o
ni
nl
o
n
g
-
t
e
rmc
u
l
t
u
r
e
s
,c
om
p
l
i
-
cating
in vitro
studies of self-renewal.
Despite recent progress in identifying
culture conditions that maintain HSC
activity
in
culture
for
a
limited
pe-
riod
of
time,
it
has
proven
exceed-
ingly
dif±cult
to
identify
tissue
cul-
ture conditions that allow a signi±cant
and prolonged expansion of progenitors
while maintaining a transplantable HSC
population.
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