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Chapter 14 Interactions Between Hematopoietic Stem and Progenitor Cells and the Bone Marrow 147

Axis), SDF-1 has important roles in HSPC homing, retention, in their reduced function, which is also associated with reduced
survival, and quiescence. Impairment SDF-1 or CXCR4 levels in transcription of SDF-1. 17,18 Of interest, upon G-CSF administration,
murine embryos results in multiple lethal defects, including lack osteoblasts rapidly expand, promoting HSPC proliferation prior to
9
of stem cell seeding of the BM. In order to circumvent lethality, their apoptosis, which in turn enables loss of HSPC retention. The
conditional knock-out models were established. Induced deletion importance of BM stromal cells in the retention of HSPCs can be
of CXCR4 in the hematopoietic system of the adult mouse or illustrated, for example, by the conditional deletion of the cell cycle
ablation of SDF-1 in the BM stroma led to severely reduced BM regulator Retinoblastoma protein (Rb). Absence of Rb in the murine
cellularity and hematopoietic stem cell (HSC) numbers, as well as hematopoietic system, as well as in the BM stroma, is sufficient
10
impaired repopulation capacity. Conditional deletion of CXCR4 to increase the numbers of circulating HSPCs, in addition to a
or SDF-1 also results in dramatically increased HSPC numbers in myeloproliferative-like disease and extramedullary hematopoiesis. 17
10
the peripheral blood and spleen, suggesting that blocking CXCR4
hampers their retention in the BM. Selective chemical antagonists
of CXCR4, such as AMD3100, were originally developed to block Involvement of Monocytes/Macrophages
CXCR4-mediated HIV infection, without any success in blocking in
vivo infection. Nevertheless, serendipitous research shows that upon Chow et al (2011) found that depletion of mononuclear phagocytes
AMD3100 administration, mouse and human HSPCs undergo rapid in mice is sufficient to mobilize HSPCs, suggesting that BM macro-
11
mobilization within hours and the mobilized HSPCs demonstrate phages promote retention of HSPCs in the BM (reviewed by Ludin
18
increased repopulation potential in vivo. et al ). Because macrophages play a crucial role in osteoblast growth
AMD3100 synergistically augments G-CSF-induced mobiliza- and survival, it has been proposed that their depletion mobilizes
19
tion. AMD3100 is the only chemokine receptor antagonist utilized HSPCs by disruption of the osteoblastic niche. By using a variety
clinically for inducing mobilization, either alone or in combination of approaches to abrogate monocytes and macrophages from the BM,
11
with G-CSF administration. AMD3100 has been shown to be an previous studies have reported that G-CSF-stimulated recruitment
12
effective mobilizing agent in murine and human clinical models, of HSPCs to the peripheral blood is dependent on direct activa-
which are known to be poor mobilizers in response to G-CSF. Mecha- tion of the monocyte lineage (Chow et al, 2011, and Christopher
18
nistically, AMD3100-induced SDF-1 release from BM stromal cells et al, 2011, reviewed by Ludin et al ). Christopher et al (2011)
to the circulation, together with an inhibitory effect in vivo, induces supported the important role of BM-resident macrophages in regulat-
rapid mobilization of HSPCs. ing the osteoblastic niche by utilizing chimeric mice that expressed
+
The essential role of SDF-1/CXCR4 signaling in HSPC reten- the G-CSF receptor only in CD68 macrophages. Upon G-CSF
tion can be inferred from the observations that following G-CSF administration, HSPC mobilization and SDF-1 downregulation in
administration, SDF-1 levels in the BM are transiently increased the BM were completely restored in these chimeric mice (reviewed
18
followed by their downregulation at both protein 7,13 and mRNA by Ludin et al ). BM-resident macrophages may therefore regulate
levels, enabling transient and local SDF-1 gradients toward the blood. SDF-1 production by BM osteoblasts and other stromal cells, which
In addition, CXCR4 upregulation is observed in immature murine generate factors that are yet to be determined. Of interest, cholesterol
BM cells following G-CSF treatment, as well as on immature human efflux pathways within mouse BM-resident macrophages are neces-
+
+
−
CD34 cells and primitive CD34 CD38 cells resident in the BM of sary to mediate this function, as a lack of cholesterol transporters
7
G-CSF–treated chimeric mice. Blocking CXCR4 or SDF-1 reduces in macrophages and dendritic cells leads to osteoblast suppression,
G-CSF–induced mobilization, thus demonstrating an essential role elevated plasma G-CSF levels, and reduction in SDF-1 production
20
for SDF-1/CXCR4 in mobilization of murine progenitors. 7 in the BM, including by MSPCs. As a result, these mice demon-
Christopherson et al reported that, compared with continuous strated increased numbers of circulating HSPCs and extramedullary
20
SDF-1 expression in the BM, SDF-1 in the peripheral blood is hematopoiesis. Intriguingly, Ludin et al (2012) has demonstrated
short-lived and is prone to proteolysis by proteases, such as CD26, the existence of an additional type of BM-resident myeloid niche cell
and metalloproteases, for example MMP-9 (reviewed by Lapidot that regulates the maintenance of primitive murine HSPCs. These
+
2
et al ). SDF-1 can directly activate the metalloprotease MMP-9, rare, activated αSMA monocytes/macrophages, which are located
which in turn cleaves and degrades this chemokine, participating near small blood sinuses, produce high levels of prostaglandin E 2
in the enhanced migration capacity and recruitment of HSPCs to (PGE 2 ) in a COX2-dependent manner; they apparently act to protect
14
the periphery. These observations suggest that SDF-1 levels in the the HSPC pool from exhaustion in steady state and upon stress by
peripheral blood are dynamically regulated during homeostasis in direct intercellular contact and reactive oxygen species (ROS) inhibi-
addition to its major role in retention of HSPCs in the BM. Repeti- tion, preventing stem cell migration and differentiation (reviewed by
18
tive daily administrations of SDF-1 for 5 consecutive days induce Ludin et al ). BM monocytes/macrophages emerge as central players
15
murine HSPC mobilization. Hampering SDF-1/CXCR4 signaling in driving HSPC retention, probably via osteoblast maintenance,
in the BM results in loss of retention, because active SDF-1/CXCR4 stromal SDF-1 expression, and PGE 2 production; however, other
signaling is required for stem cell adhesion and quiescence in the BM. immune cells of the innate immune system play additional roles, as
discussed later.
The Dynamics of Hematopoietic Stem and Progenitor
Cell Niches and Bone Marrow Microenvironment Bioactive Lipid-Induced Mobilization
During Mobilization
Other potential chemoattractants responsible for egress of HSPCs
Coupling of bone degradation and bone formation, carried out into the peripheral blood include heat-resistant bioactive lipids, in
by monocyte-derived osteoclasts and MSPC-derived osteoblasts, particular S1P, which was previously shown by Ratajczak et al (2010)
respectively, is part of the complex process of bone remodeling. to directly induce chemoattraction of human and murine HSPCs
6
Noteworthy, osteoblasts and osteoclasts maintain bone equilib- (reviewed by Golan et al ). Alvarez et al (2007) showed that S1P is
16
rium by also acting in the endosteum in the vicinity of HSPCs. a bioactive lipid implicated in cell migration, survival, proliferation,
Thus the endosteal stem cell niche is dynamically altered during and angiogenesis, as well as immune and allergic responses (reviewed
6
bone remodeling, affecting HSPC function and maintenance. by Golan et al ). Human and murine HSPCs, and BM stromal
Furthermore, accumulating evidence supports dynamic alteration and endothelial cells have been shown to express functional S1P
of the HSPC microenvironment upon stress-induced mobilization receptors, which also cross-talk with SDF-1/CXCR4 signaling, affect-
procedures. G-CSF or cyclophosphamide injections, as part of a ing migration, adhesion, homing, mobilization, development, and
clinically oriented HSPC mobilization procedure, lead to the disap- engraftment capacities. It is proposed that S1P is a crucial chemoat-
pearance or altered morphology of bone-lining osteoblasts, resulting tractant for BM-residing HSPCs, increasing ROS levels and leading