Biomedical Engineering Reference
In-Depth Information
5 The Importance of Developing Targeted Stem Cell Therapies
in Leukemia: The CML Story . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5.1 BCR-ABL Tyrosine Kinase Inhibitors in CML . . . . . . . . . . . . . . . . . . . . . . .
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5.2 CML Stem Cell Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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6 Future Challenges in Targeting LSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1 Hematopoietic Stem Cells and Normal Hematopoiesis
Stem cells are defined as cells that can differentiate into multiple different cell
types and have the ability to self-renew. There are two broad categories of stem
cells: (1) the pluripotent stem cell which can differentiate into endoderm, meso-
derm, and ectoderm, e.g., embryonic stem cells and (2) multipotent stem cells
which are lineage-specific and include hematopoietic stem cells (HSCs). The HSC
is a relatively rare cell within the bone marrow, and it is estimated that there are
between 3
10
5
and 4
10
6
HSC in the human, based on studies using limiting
dilution analysis in non-obese diabetic-severe combined immunodeficient (NOD-
SCID) mice (Wang et al. 1997) and long-term culture-initiating cell (LTC-IC)
assays (Pettengell et al. 1994). Further studies indicate that each HSC divides
approximately 70 times during its lifetime (Vickers et al. 2000) so its self-renewal
capacity is finite. By this process of cellular amplification, it is estimated that if
one stem cell divides 20 times then 1
10
6
mature cells are produced.
Hematopoiesis is the process of blood cell production. As the majority of mature
blood cells only live for a short time in the circulation (a few hours in the case of
granulocytes) before destruction by the spleen, it is necessary for the bone marrow to
produce up to 10
13
cells per day to maintain the hematopoietic system. The process
of hematopoiesis begins with the multipotent HSC which has self-renewal capacity
and the ability to differentiate into all types of mature blood cell (myeloid, erythroid,
lymphoid, etc.) through a range of lineage-committed progenitor cells (Fig. 1).
The ability of HSCs to self-renew is heterogeneous and studies on mouse bone
marrow cells indicate that 0.05% of bone marrow cells are multipotent progenitors.
This HSC population can be divided into three distinct maturational subpopula-
tions: long-term self-renewing HSCs that produce mature hematopoietic cells for
the lifetime of the mouse; short-term self-renewing HSCs; and multipotent progeni-
tors which have lost the ability to self-renew, reconstitute lethally irradiated mice for
less than 8 weeks and have increased mitotic activity (Morrison et al. 1997).
It is believed that, in steady state, only a minority of HSCs reconstitute the
hematopoietic system, with the vast majority of HSCs existing in a quiescent
state (i.e., in G
0
; out of the cell cycle). This extended period in G
0
allows the
resting HSCs time to repair any DNA damage and maintain their genetic
integrity (Lajtha 1979). Evidence for the existence of HSCs in a quiescent
state came from culture studies in which primitive human progenitor cells
remained as single cells for as long as 2 weeks and only began proliferation
after stimulation with a cytokine cocktail (Leary et al. 1989, 1992).
