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68 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 5: Structure of the Marrow and the Hematopoietic Microenvironment 69

The driving force for the migration and homing of leukocytes is including neutrophils, dendritic cells, NK cells, and T and B lympho-
the expression of chemoattractants at the site of inflammation or areas cytes. 404,405,421,499,503 The cellular specificity of the homing, localization,
of constitutive production, such as the secondary lymphoid organs or and mobilization that are driven by CXCL12 and CXCR4 are regulated
the marrow. Bacterial peptides, complement components, and cytok- by additional chemokines, adhesion proteins, and metalloproteinases
ines are produced in inflammatory sites. More than 40 different, but associated with specific hematopoietic cell types and/or the organs
structurally related, chemotactic cytokines (chemokines) can be pro- to which they home, in which they reside, and from which they are
duced by leukocytes in inflammatory sites. 495,496 Chemokines accumu- mobilized. 499,503 In the case of HSCs homing from the peripheral tis-
late on cell surfaces or in extracellular matrices through their binding sues through which they migrate, their initial entry into the lymphatic
to GAGs. 495–497 Concentrations and chemotactic activities of each cytok- vessels is driven by the lipid chemoattractant sphingosine-1-phosphate
409
ine are related to production rate, binding affinities to GAGs, presence (S-1-P). HSC display S-1-P receptors that respond to high levels in
of decoy chemokines that can compete with chemotactic activity, and the lymph compared to the peripheral tissues where S-1-P is degraded.
modulation by metalloproteinases that enhance or diminish activities For the HSCs and the marrow, multiple experiments using inhibi-
of substrate chemokines. 495 tors and antibodies with stem cell transplantation in mice and humans,
Based on the location of one or two cysteine residues in the amino parabiotic experiments with mice, and transplantation of human HSCs
terminus, chemokines are divided into four subfamilies. 224,495,496 One into immunocompromised mice (e.g., nonobese diabetic [NOD]/severe
large subfamily comprises the CXC ligand (CXCL) chemokines (e.g., combined immunodeficiency [SCID] strains) have contributed to an
platelet factor 4, IL-8, melanocyte growth-stimulating activity/GROα, understanding of some interactions of these multiple factors that influ-
506
neutrophil activating protein-2, granulocyte chemotactic protein-2), ence HSCs within the marrow. Two adhesion mechanisms that play
which mediate neutrophil migration and activation. The other large major roles in CXCL12-mediated HSCs homing to the marrow are the
subfamily comprises the CC ligand (CCL) chemokines (e.g., CCL3 binding and activation of α β integrin and selectin ligands, particularly
4 1
[MIP-1α], CCL4 [MIP-1β], [CCL5] RANTES [regulated on activation, PSGL-1, 140,468,507 on HSCs to their respective receptors, VCAM-1, and P-
normal T-cell expressed, presumed secreted], MCP-1 through MCP-5), and E-selectins on the marrow sinusoidal endothelium. 428,508 Although
which mediate mostly monocyte, and in some cases lymphocyte, che- α β integrin appears to be the major integrin on HSCs involved in the
4 1
497
motaxis. A chemokine with CXXXCL structure is fractalkine, an first step of homing, other integrins have been implicated as having sup-
endothelial transmembrane mucin–chemokine hybrid molecule that porting roles, including α β , α β , and α β or α β integrin that bind to
4 7
5 1
6 1
6 4
mediates the rapid capture, firm adhesion, and activation under phys- FN, MAdCAM-1, and laminins in the marrow. 321,421 Similarly, a coordi-
iologic flow of circulating monocytes, resting or IL-2–activated CD8 nated action between CXCR4 that has bound CXCL12 and the CD44
481
lymphocytes, and NK cells. The cytokines TNF-α and IL-1 upreg- isoform on HSCs, or another hyaladherin such as RHAMM, may
498
509
ulate fractalkine, in keeping with the need to rapidly recruit effector provide a source of adhesion for HSCs to hyaluronic acid on marrow
cells at sites of inflammation. The chemokine receptors on the sur- endothelial cells in the homing process. In cord blood cells enriched for
face of leukocytes are coupled to G proteins that initiate signaling for HSCs, the colocalization and cooperative activity of the endolyn with
chemotaxis upon chemokine ligand binding. 495,496 The chemokine CXCR4, α β , and α β integrin appears to enhance HSCs homing to the
5 1
4 1
475
receptors for the two large subfamilies bind those members such that marrow in response to CXCL12. CXCR4 has also been colocalized
CXCLs bind CXCRs and CCLs bind CCRs. However, within these two in lipid rafts on HSCs with Rac-1, a member of the receptor-associated
510
subfamilies is significant redundancy and promiscuity in chemokine- RhoGTPases. The RhoGTPases have two members, Rac-2 and RhoH,
receptor binding. Table 5–3 gives a detailed listing of chemokine recep- that are hematopoietic specific and, with other more widely expressed
tors and the cellular targets and ligands interacting with each receptor members such as Rac-1, Cdc42, and Rho A, are downstream effectors of
511
subgroup. CXCR4, β -integrin, and KIT signaling in HSCs. The various RhoGT-
1
A major exception to this redundant and promiscuous chemokine- Pases modulate actin polymerization and lead to cytoskeletal changes
receptor interaction is the specific binding of CXCL12/stromal cell-de- that are required for survival, proliferation, homing, and mobilization
rived factor (SDF)-1α to its receptor CXCR4, which is associated with of HSCs and their progeny. In the homing of HSCs, the RhoGTPase-
homeostatic maintenance of cell populations, including HSCs and their mediated signaling provided by the coordinated action of CXCR4, β
1
progeny in the marrow. 496,499 CXCL12 can bind to one other chemok- integrins, and CD44 leads to the rolling, arrest, and transmigration of
ine receptor (CXCR7), but mouse knockout experiments show that the marrow sinus endothelial cells.
CXCL12 null and CXCR4 null mice have embryonic lethal phenotypes Once the HSCs have migrated across the sinusoidal endothelial
that are markedly similar whereas CXCR7 null mice have postnatal cells, they migrate further within the marrow in response to CXCL12.
lethality due to cardiovascular defects; CXCR7 may have a role in lig- Using fluorescent SLAM-labeled markers for the identification of HSC
and sequestration but not in hematopoiesis. 496,500–502 CXCL12 is pro- in murine transplantation experiments, the homing of HSCs in the
duced by the bone, endothelial, perivascular reticular cells and some marrow cavity is associated with reticular cells that harbor the highest
hematopoietic cells in the marrow, and its receptor CXCR4 is expressed numbers of CAR cells in the marrow. The majority of CAR cells are
132
on various hematopoietic and mature blood cells. 468,499,503 The murine in the perivascular areas to which the HSCs home. Another factor that
52
gene Cxcl12 was floxed, allowing conditional deletion by various Cre may contribute to perivascular homing, especially following stress, such
transgenics expressed in mesenchymal progenitor cells. Conditional as lethal irradiation, is the ability of the marrow sinusoidal endothe-
deletion of Cxcl12 in mineralizing osteoblasts resulted in no obvious lial cells that express CXCR4 that binds circulating CXCL12 and trans-
phenotype whereas deletion in Osterix-Cre–expressing reticular (CAR ports it into the perivascular areas of the marrow. 503,512 A second area
cells) and osteoblast cells resulted in constitutive HSC mobilization in the marrow to which HSC home is the endosteal niche because of
512
and loss of B-lymphoid progenitor cells. 504,505 The Cre transgenics that the proximity of these endosteal areas to perivascular areas, as well as
delete floxed Cxcl12 alleles have complicated patterns of expression the abundant CXCL12 production by osteoblasts and osteoclasts. 134,165
and current evidence supports a more important role for the perivas- Thus, two HSC niches are recognized in the marrow—perivascular
505
cular niche in the homing of HSCs. Hence, mouse genetics and phar- and endosteal—with HSCs in the perivascular areas more likely to
macologic inhibition show that CXCL12 and CXCR4 are involved in proliferate, differentiate, and mobilize into the blood than HSCs in the
the trafficking of HSCs, committed progenitor cells, and mature cells, endosteal areas. 75,150,512

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