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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 P-selectin glycoprotein ligand (PSGL)-1, which binds to all three CD157 is expressed on marrow stroma, T and B cells, and myeloid cells.
selectins (see Table 5–2). These proteins are responsible for leuko- It promotes pre–B-cell adhesion and growth. Cadherins are large
483
cyte rolling over endothelial surfaces and tethering, thereby allowing molecules involved in cell–cell junctions and vascular integrity. CD144
integrin-mediated firm adhesion to the endothelium and mediating (VE-cadherin) is expressed on CD34+ hematopoietic and endothelial
cellular homing events using specialized high endothelial venule lym- progenitor cells and is an important molecule for trafficking of HSCs
phocyte homing sites. 140,467,468 In addition to their role in HSC homing in in fetal tissues and for the maintenance of HSC self-renewal. 115,484,485
the marrow, E-selectin and P-selectin can promote quiescence in HSC Downregulation of VE-cadherin is associated with crosslinking of
and induce apoptosis of late-stage myeloid progenitors while promoting VCAM-1, resulting in enhanced transendothelial migration of CD34+
120
the expansion (P-selectin) or differentiation (E-selectin) of short-term cells in response to CXCL12. Although N-cadherin expression by
repopulating cells. 469 both HSC and osteoblasts has been proposed to play a role in their inter-
actions, experimental results in knockout mice do not support such a
SIALOMUCINS role. 11,486
Three members of the CD34 family—CD34, podocalyxin, and endo-
glycan—are expressed on vascular endothelium, HSCs, and various CELLULAR HOMING
hematopoietic cell lineages. When expressed on lymphoid high Leukocyte trafficking and migration have been central to understand-
470
endothelial venules, these sialomucins are receptors for L-selectin, ing mechanisms of tissue homing. One of the best studied processes
but their differential glycosylation in hematopoietic cells prevents L- is lymphocyte homing to secondary lymphoid organs via special-
selectin binding and results in their reducing nonspecific adhesion and ized high endothelial venules (HEVs). Generally, leukocytes home to
potentially enhancing mobility. Although its function has not been areas of inflammation by adhering to the endothelium and migrating
determined, endomucin is another CD34-like sialomucin expressed in between intercellular spaces by a sequence of specific events that begins
endothelium and in HSCs. In T lymphocytes, where it affects mobil- with tethering of the leukocytes to the luminal surface of the endothe-
471
ity, CD43 (leukosialin) acts in concert with PSGL-1 and binds both lial cells. In the secondary lymphoid organs, tethering is mediated
487
P-selectin and E-selectin. 472,473 CD43 in neutrophils can foster adhesion by L-selectin/CD62L receptor on the surface of naïve lymphocytes
when binding to E-selectin on endothelial cells, but it inhibits adhesion that binds a complex carbohydrate determinant, 6-sulfo-sialyl Lewis
in most instances. CD43 can also regulate hematopoietic progenitor X, on glycoproteins called peripheral node addressins, such as CD34,
473
survival. CD162 (PSGL-1), a sialomucin that binds all three selec- podocalyxin, and endomucin. 488,489 P-selectin and E-selectin are upreg-
474
tins, is important in leukocyte trafficking and stem cell homing. 467,468,470 ulated on the endothelial cell surface in response to various inflamma-
CD164 (endolyn), another sialomucin receptor displayed on HSCs, tory cytokines, where they bind their respective receptors, PSGL-1 and
forms a complex with CXCR4, VLA-4, and VLA-5 on the leading edge CD44 on leukocytes. 466,490 Tethering results in rolling of the leukocytes
of migrating HSCs after exposure to FN-bound CXCL12, indicating a along the endothelial surface. Interactions of VLA-4 and α β integrin
4 7
role for CD164 in the homing of HSCs. CD166 (hematopoietic cell on the surface of lymphocytes with their respective ligands VCAM-1
475
antigen [HCA], activated leukocyte adhesion molecule [ALCAM]) and MAdCAM-1 on HEVs may also mediate rolling. Rolling of neu-
467
is expressed on HSCs and osteoblasts and is required for long-term trophils is slowed further by PSGL-1 and L-selectin activation of other
engraftment potential of donor HSCs in murine transplantation mod- adhesion molecules that include the β integrins α β (LFA-1) and α β
2
L 2
M 2
els, probably through homophilic interaction. 476–478 CD166’s only other (Mac-1). 490–492 These β integrins, in turn, bind ICAM-1 on endothelial
2
ligand is CD6. 477,479 cells. The rolling leukocytes also receive signals through surface G-
protein–coupled receptors that bind chemokines in the heparan sulfate
HYALADHERINS proteoglycans on the endothelial cells. 490–492
The fifth subgroup listed in Table 5–2 is the cartilage-related proteogly- The interaction of PSGL-1, L-selectin, integrins, and G-protein–
can, CD44, also known as the lymphocyte homing cell adhesion molecule coupled receptors with their endothelial ligands leads to cytoskeletal
(HCAM). This adhesion receptor, which binds the hyaluronic acid in changes with arrest of rolling and adhesion to the endothelium. The
the marrow matrix and can be a receptor for E-selectin, is expressed on adherent leukocytes undergo a rapid diapedesis, with migration either
neutrophils, lymphocytes, erythroblasts, and HSC. 467,468 CD44 displayed through or between the endothelial cells into the abluminal interstitium.
on HSCs facilitates their homing and adhesion to the marrow and plays At the interface with the adherent leukocyte, ICAM-1 and VCAM-1 in
a role in their mobilization in response to G-CSF. 467,468,480 Studies with the endothelial cell are concentrated in a cup-like, caveolin-rich struc-
CD44-deficient mice show no defects in HSC homing and growth, and ture that internalizes ICAM-1. 492–494 This caveolin-rich structure is linked
no decrease in hematopoiesis, suggesting that another hyaladherin to the endothelial cell cytoskeleton through vimentin. The internaliza-
481
receptor may compensate for the absence of CD44. The other hyalad- tion of the ICAM caveolae leads to the formation of a channel through
herin receptor on HSC is the receptor for hyaluron-mediated mobility the cell to the abluminal surface. When leukocytes follow a paracellular
(CD168/RHAMM), 467,481 which does provide hyaluronic acid binding route through the endothelium, they require the coordinated activity
482
by neutrophils under inflammatory conditions in CD44 deficiency. of multiple adhesion proteins. These include PECAM-1, CD99, JAM
Thus, CD44 and CD168/RHAMM may provide redundant hyaluronic proteins, and VE-cadherin, each of which mediates homophilic inter-
acid binding in HSC. actions at intercellular junctions between endothelial cells, and ICAM-
2. 492–494 Although the roles of these proteins are uncertain, antibody
inhibition and knockout mice demonstrate that they are necessary for
OTHER ADHESION MOLECULES the unidirectional migration of the leukocyte through the endothelium.
CD38 is an adhesion receptor that binds the CD31 receptor and matrix PECAM-1, CD99, and JAM-C are expressed on leukocytes and may be
hyaluronan. It is expressed on early T and B cells and subsets of CD34+ involved in homophilic interactions between the migrating leukocyte
hematopoietic progenitors. Similar to CD38, the stromal adhesion and the endothelial junction. LFA-1 and Mac-1 on leukocytes can bind
483
receptor BST-1 (CD157) is an adenosine diphosphate-ribosyl cyclase and interact with ICAM-2 and JAM-A on endothelium, whereas leuko-
that is involved in regulation of intracellular calcium concentrations. cyte VLA-4 can interact with endothelial JAM-B.

Kaushansky_chapter 05_p0051-0084.indd 68 9/19/15 12:11 AM