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66 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 5: Structure of the Marrow and the Hematopoietic Microenvironment 67

409
the blood. HSCs display multiple adhesion and cytokine receptors (MAdCAM)-1, like the integrin α β /VCAM-1 receptor pair, contribute
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that allow them to attach to cellular and matrix components within the equally to the homing of HSC to the marrow. 428,429
430
marrow sinusoidal spaces. 275,277,410–412 Such attachments facilitate HSC Integrins are signaling molecules. After engaging their lig-
homing and lodgment in the marrow and provide the cell–cell contacts ands, or subsequent to activation by monoclonal antibodies, multiple
required for HSC survival and steady-state proliferation, as shown by events (tyrosine phosphorylation of focal adhesion kinase, paxillin, and
413
membrane-bound SCF regulation of HSC lodgment in the endosteal ERK-2) are triggered (outside–in signaling), culminating with Ras acti-
433
marrow region. 414 vation. 431,432 Integrin receptor crosstalk with other adhesive receptor
In most lineages, differentiated cells are released from the marrow, members, such as the immunoglobulin superfamily (NK cell–T cell
circulate in the blood, and eventually home to the marrow. In some cell [α β /DYNAM-1], CD34+endothelial cell PECAM-1, 434–436 or selec-
L 2
437
types, the circulating cells will differentiate further in peripheral organs tins, also results from outside–in signaling events that regulate recep-
such as B lymphocytes in the lymph nodes and spleen, monocytes in the tor-binding affinity 438,439 and mediates inhibitory signals for erythroid,
tissues, and T lymphocytes in the thymus. After a period of residence myeloid, and lymphoid progenitor growth. 440–443 Integrin binding of
in these secondary lymphoid organs, some lymphocytes travel through their respective receptors, such as α β /VCAM-1 or α β /FN, in early
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the lymph and blood, homing to the marrow, where they become func- CD34+ progenitors enhances viability and preserves their long-term
444
tioning mature cells, such as plasma cells and CD4 and CD8 mature repopulating ability. In studies of isolated SP cells, high expression
T lymphocytes. 199,200,204 Mature and band forms of neutrophils exit the of the vitronectin receptor α β (CD51/CD61) is associated with qui-
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marrow, circulate in the blood and, if not recruited to a site of inflam- escence and long-term repopulating ability. Conversely, expression
445
mation, home as senescent cells to the marrow by the CXCL12/CXCR4 of the α integrin is associated with only short-term repopulating
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405
mechanism described in the preceding “Granulocytes” section. capacity. 446
Senescent erythrocytes are also removed from circulation through a
mechanism that involves binding surface ICAM-4 to integrin α β (lym- IMMUNOGLOBULIN SUPERFAMILY
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phocyte function-associated antigen [LFA]-1) on macrophages in the
415
spleen and marrow. Mature leukocytes that participate in inflamma- The immunoglobulin superfamily designates a group of molecules con-
tory reactions, such as the lymphocytes, monocytes/macrophages, and taining one or more amino acid repeats also found in immunoglobu-
eosinophils, exit the circulation in areas of infection, allergic reactions, lins and includes PECAM-1 (CD31), ICAM-3/R (CD50) and ICAM-1
or injury. Table 5–2 lists the adhesive receptors and their ligands pres- (CD54), LFA-3 (CD58), ICAM-2 (CD102), VCAM-1 (CD106), KIT
ent on HSCs, progenitor cells, and components of the hematopoietic (CD117), and LW/ICAM-4 (CD242) (see Table 5–2). 447–461 VCAM-1
microenvironment, but receptor–ligand interactions that regulate the is upregulated by inflammatory cytokines, IL-4 and IL-13. 462,463 Immu-
trafficking of mature leukocytes are not exhaustively listed. 416,417 noglobulin-like adhesion molecules also include NCAM, a neural
cell-adhesion molecule that binds lymphocytes but not hematopoietic
INTEGRINS progenitors; Thy1, a stem cell antigen; major histocompatibility com-
plex classes I and II; and CD2, CD4, and CD8 (see Table 5–2). LW/
247
Integrins mediate important cellular functions, including embryonic ICAM-4 on erythroblasts binds the α component of integrins on mac-
v
development, cell differentiation, and adhesive interactions between rophages in EBIs, whereas the normal function of Lutheran red blood
94
hematopoietic cells and inflammatory cells and surrounding vascu- cell antigen, Lu/B-CAM (CD239), which binds the α component of
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lar and stromal microenvironments. 411,412,418 Integrins are divalent laminin and is expressed late in erythroblast differentiation, is uncer-
cation-requiring heterodimeric proteins (18 α subunits and 8 β sub- tain. The sialic acid-binding immunoglobulin-like lectins (Siglecs) are
461
units) subdivided by the β-chain component. Table 5–2 indicates that a family of surface proteins found on lymphocytes and myeloid cells
α-chains can associate with more than one β-chain subunit. The prin- that bind sialic acid residues of glycoproteins. Some Siglecs are evo-
464
cipal integrin receptors of the β subgroup involved in HSC-endothe- lutionarily conserved, such as Siglec-1 (sialoadhesin), which is highly
1
lial and HSC-stromal interactions are α β (VLA-4), α β (VLA-5), and expressed on macrophages, including the central macrophages of EBIs,
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α β (LFA-1) of the β subgroup. α β -based stromal adhesion events and CD22, a coreceptor on B-lymphocytes. The remaining Siglecs,
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2
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regulate erythropoiesis in the stages after EPO dependence. Gran- which are phylogenetically evolving rapidly, include CD33, which is
419
ulopoiesis is stimulated by α β activation by marrow stromal cells in expressed in lymphocytes and in all stages of myeloid cells where it is a
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cooperation with PECAM-1 (CD31), an immunoglobulin superfamily commonly used marker for acute myeloid leukemia.
member. Antibodies against α or small molecule antagonists can
420
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mobilize hematopoietic stem and progenitor cells into the peripheral
circulation. The high expression of α β in granulocytic precursor LECTINS (SELECTINS)
421
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cells and newly formed granulocytes has an important role in their Homing of stem cells requires lectin receptors with galactosyl and
adherence to VCAM-1 in the marrow, whereas the downregulation of mannosyl specificities. 465,466 The selectins are a family of adhesion
α β in the more mature neutrophils works in concert with CXCL12/ molecules, each containing type C lectin structures. The leukocyte
467
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CXCR4 for their release into the blood. The α β integrin on B lym- selectin (L-selectin, CD62L) is expressed on hematopoietic stem and
422
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phocytes is important for interactions with the VCAM-1 on the stromal progenitor cells and mediates adhesive interactions with other receptors
cells in the B-lymphocyte niche, both in early B-lymphocyte develop- (addressins), such as the CD34 sialomucin present on specialized endo-
ment prior to migration out of the marrow and in later development of thelium, using sialylated fucosyl-glucoconjugates (see Table 5–2).
259
plasma cell precursors that have reentered the marrow. An acquired The CD34 receptor on stem cells, however, does not bind L-selectin,
259
199
defect in stromal function, characterized by a deficiency in VCAM-1 as a putative L-selectin ligand may exist on these cells but is yet to be
and IL-7 expression, 423–425 accounts for the delayed B-lymphoid recon- defined. The selectin family also contains CD62E, an E-selectin con-
stitution seen after marrow transplantation. During thrombopoiesis, stitutively expressed on the marrow sinusoidal endothelium that reg-
CXCL12 induces VCAM-1 in the marrow sinusoid endothelial cells ulates transmigration of leukocytes and CD34+ stem cell homing. The
426
that mediates the binding of the megakaryocytes to the endothelium. third member of this family is P-selectin, which is found on platelets. P-
427
Integrin α β and its receptor, mucosal addressin cell adhesion molecule selectin can bind HSCs using a mucin receptor, CD162 also known as
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Kaushansky_chapter 05_p0051-0084.indd 66 9/19/15 12:11 AM