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146 Part II Cellular Basis of Hematology

increased migration and adhesion via very late antigen (VLA)-4 and
VLA-5 integrins. Moreover, the homing of murine progenitor cells
to the BM of mice deficient in P- and E-selectin was impaired,
demonstrating the crucial role of adhesion interactions for proper
homing, allowing HSPC rolling on the BM endothelium and reten-
tion in their stromal supportive niches. Interestingly, SDF-1 is not
the only chemoattractant factor for HSPC homing; previous studies
have shown that the chemoattractant lipid sphingosine-1-phosphate
(S1P) has a role in inducing murine HSPC homing to the BM
5
by increasing progenitor adhesion to stromal cells. S1P, together
with SDF-1, was indeed reported to have a synergistic effect on the
migration of hematopoietic progenitor cells; however, this finding
was later refuted by Ryser et al, showing no additive effect when both
chemoattractants are added to the same plate. In contrast, this group
showed that overexpression of S1P 1 (S1P receptor) on immature
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human CD34 cells strongly reduces their migration toward a gradi-
ent of SDF-1 and in vivo homing via inhibition of CXCR4 signaling
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(reviewed by Golan et al ).
Taken together, manipulation of SDF-1 levels in the target organ
and CXCR4 on the surface of transplanted stem cells can be used
to navigate stem cells in vivo. Enhanced SDF-1 production by BM
stromal cells after host preconditioning, crossing the blood–BM
barrier, and activation of the adhesion machinery are required for
HSPC attachment to BM-supporting niches, allowing their subse-
quent self-renewal and differentiation (see Fig. 14.1).
HEMATOPOIETIC STEM AND PROGENITOR CELL
MOBILIZATION: A DYNAMIC MULTIFACETED PROCESS

HSPCs are actively retained in the BM via adhesion interactions with
their stromal microenvironment. In the BM, they undergo extensive
proliferation and differentiation, giving rise to all mature leukocyte
and erythrocyte reservoirs, and replenishing the blood with new cells.
Interestingly, in addition to mature leukocytes, low levels of HSPCs
are also released to the blood as part of steady-state homeostasis.
Fig. 14.1 HOMING OF TRANSPLANTED HEMATOPOIETIC STEM During stress situations and upon demand of accelerated hemato-
AND PROGENITOR CELLS TO THE BONE MARROW. Following poiesis, HSPC egress is dramatically augmented in a process termed
7
transplantation, navigating HSPCs from the circulation roll and adhere (1) recruitment. Enhanced HSPC egress occur as part of host defense and
to BM endothelial cells. This process is followed by transendothelial migra- repair mechanisms following various stress situations, such as inflam-
tion across the physical blood–BM barrier (2). HSPCs interact with MSPCs mation (mimicked by lipopolysaccharides [LPS]; endotoxins found
via surface SDF-1/CXCR4 signaling, which is a key regulator of stem cell in the outer membrane of Gram-negative bacteria, or endotoxin
homing and adhesion to the BM-supportive niche, an essential process for administration), bleeding, and administration of cytotoxic agents,
HSPC lodgment and retention (3). BM, Bone marrow; HSPC, hematopoietic such as chemotherapy.
stem and progenitor cell; MSPC, mesenchymal stem and progenitor cell. Stem and progenitor cell recruitment is achieved by clinical
mobilization protocols, such as repeated G-CSF stimulations, which
are used to expand the HSPC pool and to harvest the cells from the
reduced homing of transplanted HSPCs to the BM, demonstrating blood for clinical transplantation.
the crucial role of SDF-1 in homing of HSPCs. 3 Stress-induced HSPC recruitment and mobilization is a complex
Administration of high doses of SDF-1 induce cell survival and process involving essential motility mechanisms, activities of various
quiescence, whereas low doses promote cell motility, proliferation, cytokines, chemoattractants (e.g., SDF-1), proteolytic enzymes,
4
and migration (reviewed by Lapidot and Kollet ). Accordingly, and other extrinsic factors that enable detachment of HSPCs from
Cashman et al showed that in vivo treatment with high doses of their BM niches. These BM niches prevent HSPC migration and
SDF-1 increased engraftment of human repopulating cells (reviewed proliferation via adhesion interactions, and therefore disconnecting
4
by Lapidot and Kollet ). such interactions are essential for HSPC motility, leading to their
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A single injection of human SDF-1 to nonirradiated β2m egress. Recent evidence for the involvement of other cellular players,
NOD/SCID mice increased homing of transplanted human mobi- such as neutrophils, macrophages, and osteoblasts, in the regulation
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lized peripheral blood and cord blood (CB) CD34 cells to the of stress-induced HSPC recruitment will be discussed.
murine BM. It was found that the noncleaved active form of SDF-1 This part of the chapter summarizes insights regarding mechanistic
can cross the BM endothelium to the BM in a CXCR4-dependent aspects of mobilization, as well as recent data on steady-state and rapid
manner. This increase in SDF-1 level in the BM functionally enhances HSPC mobilization mechanisms. Currently, new rapid mobilization
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the homing capacity of transplanted human CD34 progenitors of protocols using CXCR4 antagonists, such as AMD3100, together
2
NOD/SCID mice (reviewed by Lapidot et al ). According to this with G-CSF, lead to higher levels of HSPC mobilization. 8
data, enhanced CXCR4 expression as well as inhibition of SDF-1
degradation is important to enable a stable chemotactic response,
directing the homing of HSPCs to the BM. The SDF-1/CXCR4 Axis in Hematopoietic Stem and
Another important cytokine regulating progenitor cell homing Progenitor Cell Mobilization
is stem cell factor (SCF; also termed c-Kit ligand), which plays an
important role in hematopoiesis. Prestimulation of human or murine As noted earlier in this chapter (in the section Mechanisms Regu-
HSPCs with SCF improved their in vivo homing abilities through lating HSPC Homing: The Essential Role of the SDF-1/CXCR4