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C H A P T E R 14

INTERACTIONS BETWEEN HEMATOPOIETIC STEM AND

PROGENITOR CELLS AND THE BONE MARROW: CURRENT

BIOLOGY OF STEM CELL HOMING AND MOBILIZATION

Eman Khatib-Massalha, Kfir Lapid, Karin Golan, Orit Kollet,
Shiri Gur-Cohen, Menachem Bitan, Anju Kumari, and Tsvee Lapidot

The hallmarks of hematopoietic stem and progenitor cells (HSPCs) chemokines. The small blood vessels in both human and murine
are their migration, bone marrow (BM) homing, and repopulation BM, the sinusoids, in which transendothelial migration is thought
potential. These primitive cells are continuously released at low levels to take place, are composed of specialized cell structures that regulate
from the BM to the circulation as part of steady-state homeostasis, and cell trafficking.
at accelerated rates during stress hematopoiesis situations such as injury The homing process is initiated by a SDF-1/CXCR4 guiding
or inflammation as part of host defense and repair mechanisms. Migra- signal, leading to firm adhesion and docking to the vascular sinusoi-
tion of hematopoietic stem cells from the blood, across the endothelial dal wall (Fig. 14.1), which induces cytoskeleton rearrangement and
vasculature to their BM niches, requires active navigation, a process activation of integrins (e.g., VLA-4) and metalloproteinases (e.g.,
termed homing. The ability of HSPCs to home to the BM is the first MMP-2/9). These cellular alterations are followed by transmigra-
and essential step for clinical transplantation. Physiologic stress caused tion across the physical BM–blood endothelial cell and extracellular
2
by bleeding, injury, or infection induces massive proliferation and matrix barriers (reviewed by Lapidot et al ).
differentiation of HSPCs in the BM, which is accompanied by increased HSPCs are localized and anchored in special stromal niches via
progenitor cell egress and recruitment to the circulation. This process is adhesion interactions, which provide them with signals that prevent
mimicked in clinical mobilization protocols, to increase the HSPC pool their motility, proliferation, and uncontrolled differentiation. Stromal
in the circulation and to harvest stem cells for clinical transplantation CXCL12 abundant reticular (CAR) cells express the highest levels
protocols. The transplanted stem cells actively home to the recipient of SDF-1, which is essential for murine stem cell quiescence and
BM and repopulate it by extensive proliferation and differentiation, maintenance; they serve as stem cell niche cells. While murine stem
while maintaining their self-renewal potential and motility capacity, cell homing can be investigated in genetically matched recipient
enabling them to egress back to the circulation. These processes involve mice without rejection of donor cells, functional preclinical immune-
the stromal chemokine SDF-1 (also termed CXCL12) and its major deficient animal models have been developed to study human stem
receptor CXCR4, which regulate stem cell motility and proliferation, as cell homing and engraftment.
well as their adhesion, retention, and quiescence. HSPC mobilization
can be clinically induced by a variety of cytokines, such as the myeloid
cytokine granulocyte colony-stimulating factor (G-CSF), the CXCR4 Mechanisms Regulating HSPC Homing: The Essential
antagonist AMD3100, and by DNA-damaging chemotherapy drugs, Role of the SDF-1/CXCR4 Axis
such as cyclophosphamide (Cy).
2a
HSPCs in the BM continuously replenish the blood with new As discussed by Cottler-Fox et al, SDF-1/CXCR4 interaction and
maturing myeloid and lymphoid immune cells with a finite life downstream signaling have been implicated in retention, migration,
span throughout life. Some of the circulating leukocytes are short homing, and mobilization of HSPCs during steady-state homeostasis,
2
lived, in particular neutrophils, which rapidly age within a few hours as well as during injury (reviewed by Lapidot et al ). Both human and
and home back to the BM across the physical blood–BM barrier, murine BM stromal cells, including endothelial cells and endosteal
resulting in their apoptotic cell death. SDF-1/CXCR4 signaling is bone-lining osteoblasts, express and secrete high levels of SDF-1,
also involved in neutrophil retention in the BM, while the CXCL2/ observed in regions rich in HSPCs.
CXCR2 signaling pathway is involved in neutrophil trafficking from Concomitantly, the expression of CXCR4 on circulating HSPCs
the BM to the circulation. is very dynamic and allows their direct chemoattraction toward high
This chapter discusses recent findings concerning the biology of levels of SDF-1 found in the BM endothelium, thus facilitating
HSPCs and mature leukocyte (especially neutrophil) homing and the homing process (see Fig. 14.1). CXCR4-dependent homing
mobilization, emphasizing the major roles of the SDF-1/CXCR4 is also observed in aging neutrophils, which express high levels of
and CXCL2/CXCR2 signaling cascades in their dynamic retention CXCR4 and migrate back to the BM across the mechanical barrier
and mobilization. in order to engage cell death. Genetic overexpression of CXCR4 or
cytokine-induced increased surface expression of CXCR4 (e.g., by
HEMATOPOIETIC STEM AND PROGENITOR hepatocyte growth factor [HGF]) enhanced the homing capacity
2b,2c
showed that
of transplanted human HSPCs, while Kollet et al
CELL HOMING administration of neutralizing anti-CXCR4 antibodies impaired
+
the homing of immature human CD34 stem and progenitor
Migration of HSPCs from the circulation and their extravasation cells to the BM of transplanted immunodeficient mice. Given the
across the physical barrier of the blood vessels to the BM require important clinical challenge of improving HSPC engraftment and
an active navigation, a process termed homing. HSPC homing is repopulation, upregulation of CXCR4 expression is a promising
the critical first step leading to successful clinical engraftment in the approach.
ablated BM of transplanted recipients, which is the predominant Murine BM stem cell niches contain a rare population of mes-
physiologic site of hematopoiesis. 1 enchymal stem and progenitor cells (MSPCs), which express the
The BM endothelium is the first anchoring site for homing cells, highest levels of SDF-1 in the BM microenvironment. Depletion of
exposing them to presented adhesion molecules and stimulating stromal-supporting niche cells results in defective hematopoiesis and

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