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62 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 5: Structure of the Marrow and the Hematopoietic Microenvironment 63

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such as IL-3, SCF, and thrombopoietin (TPO) augment the magnitude and laminin-10 (α β γ ) in the marrow. Stromal cells in cultures and
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of FN-mediated HPC adhesion and migration. 285–288 Functional effects cytokine-expanded CD34+cells also express laminin β , which is found
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of FN within the marrow ECM include decreased erythroblast FN adhe- in the pericellular space in marrow and intracellularly in megakary-
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sion as differentiation progresses 274,283 with modulation of erythroid cell ocytes. Laminin-γ chain expression, which is unique to marrow-
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differentiation dependent upon competing binding of α β integrin derived stromal cells, colocalizes with α smooth-muscle actin in mar-
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with FN in the ECM and with central macrophages in erythroblastic row and is not expressed in endothelial cells or megakaryocytes. 320
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islands. Binding of collagen I in the marrow ECM by megakaryo- Integrins α β and α β are receptors for laminin-10/11 and
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cytes leads to their spreading and inhibition of proplatelet formation laminin-8. Laminin-10/11 (α β γ /γ β γ ) and FN bind CD34+ and
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by a mechanism involving FN induction and secretion with polymer- CD34+ CD38–progenitors, whereas laminin-8 (α β γ ) and lami-
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ization via cosecreted factor XIII-A. FN is required for expression of nin-10/11 facilitate CXCL12–mediated transmigration of CD34+
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gelatinase in macrophages and regulates cytokine release by M-CSF– cells. In mouse repopulation studies, antibodies that block the α
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activated macrophages and chondrocytes. 293 components of laminin receptors decreased the homing of HSCs and
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colony-forming units–granulocyte-macrophage (CFU-GM). When
Tenascin combined with antibodies to the α component of integrins, antibodies
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The fibrillar glycoprotein tenascin-C is found in the microenvironment that block the α components synergistically decreased marrow homing
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surrounding maturing hematopoietic cells. 218,294 Tenascin-C has distinct of the short-term, multipotent repopulating cells. In contrast to this role
functional domains that promote hematopoietic cell adhesion to ECM of these integrin receptors in the homing of HSCs, a 67-kDa, noninte-
proteins or mediate a strong mitogenic signal to marrow mononuclear grin laminin receptor is upregulated in HSCs following G-CSF stimu-
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cells. Although tenascin-C–deficient mutant mice appear to have nor- lation and plays a significant role in their mobilization. This 67-kDa
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mal steady-state hematopoiesis, colony-forming capacity of marrow is nonintegrin receptor for laminin also has a role in the marrow homing
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markedly decreased, marrow regeneration capacity after cytoreduc- of burst-forming units–erythroid (BFU-Es), early-stage erythroid pro-
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tive agents is decreased, and retention of T-lymphocyte progenitors genitors that circulate in the blood. On the other hand, the Lutheran
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is impaired. This last effect is mediated through the α β integrin on blood group glycoproteins serve as receptors for the α integrin compo-
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T-lymphocytes progenitors, but effects on HSCs and early hematopoi- nent of laminins on the late-stage erythroid cells. Laminin promotes
etic progenitors is mediated by a different mechanism. Mutant tena- the M-CSF–dependent proliferation of marrow-derived macrophages
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scin-C–deficient animals also display decreased FN in their marrow, via the α -integrin subunit, and α β mediates mast cell adhesion to
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suggesting a possible mechanistic interaction between tenascin-C and laminin. 326
FN in the marrow microenvironment. 298
Thrombospondin
Collagen The TSPs are secreted matrix glycoproteins that modulate cell function
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Collagen types I and III are associated with microvascular walls, by altering cell–matrix interactions. TSP1, a multifunctional ECM
whereas collagen type IV is confined to basal lamina beneath endo- protein initially identified in platelet α granules, has domains that inter-
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thelial cells. 160,299 Marrow-derived capillary networks grow in collagen act with collagen and FN and may participate in HSC lodgment. TSP
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gel cultures, inhibition of collagen synthesis reduces hematopoiesis activates TGF-β which results in a stimulatory effect on NK cells.
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in vitro, and collagen-based scaffolds are most effective for in vitro TSP binds to matrix heparan sulfates and inhibits osteogenic dif-
three-dimensional models of the hematopoietic microenvironment. ferentiation. 331,332 Receptors on hematopoietic and nonhematopoietic
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Marrow-derived fibroblasts and stromal cells synthesize collagens I, cells can interact with TSP, including CD36 and the cutaneous lym-
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III, IV, V, and VI. Collagen VI binds von Willebrand factor and is phocyte antigen-1 protein of the CD36/LIMP II gene family. CD36
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a strong cytoadhesive component of the marrow microenvironment. is expressed during erythroid and megakaryocytic maturation. TSP
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Erythroid and granulocytic progenitors adhere to collagen type I in stimulates matrix metalloproteinase-9 activity in endothelial cells
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vitro. Collagen type XIV, another fibril-associated collagen, promotes and is chemotactic to monocytes. A 140-kDa fragment of TSP1
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hematopoietic cell adhesion of myeloid and lymphoid cell lines. In binds bFGF, and TSP1 acts as a scavenger for matrix-associated angio-
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situ immunolocalization of ECM proteins in murine marrow shows that genic factors (fibroblast growth factor 2, VEGF, HGF), underscoring
collagen types I and IV and FN localize to the endosteum. Megakary- its antiangiogenic properties. 338,339 Mice deficient in TSP2 demonstrate
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ocyte binding to collagen I that induces FN secretion and polymeriza- that TSP2 is taken up in an integrin-dependent manner within the mar-
tion enhances the α β -mediated collagen binding by megakaryocytes, row and is necessary for the release of functionally competent plate-
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permitting increased megakaryocyte adhesion and migration, which lets by megakaryocytes. The 21-amino acid, C-terminal peptide of
are also mediated by other megakaryocytic collagen receptors including TSP4 stimulates proliferation of multiple types of early hematopoietic
glycoprotein VI and discoid domain receptor 1(DDR1). 309 progenitors through the regulator of differentiation 1 (ROD1) nuclear
receptor and increases erythropoiesis in mice. 341
Laminin
Laminins, multidomain glycoproteins with mitogenic and adhesive Vitronectin
sites, are major components of the ECM and basement membranes. Vitronectin, a major cytoadhesive glycoprotein, is present in plasma
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Laminin interactions with collagen type IV and basement membrane and the interstitial matrix of tissues. It interacts with a vast number of
components such as proteoglycans and entactin regulate leukocyte ECM components, cytokines, growth factors and proteolytic enzymes
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chemotaxis. 312,313 CD34+ granulocytic progenitors, mature mono- in vitro and in vivo. Vitronectin also binds to several α -containing
v
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cytes, and neutrophils adhere to laminins. The role of laminins integrins, including the integrin α β receptor (CD51) on fibrob-
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within the cytomatrix may be to strengthen adhesive interactions with lasts, endothelial cells, osteoclasts, 343,344 and mature hematopoietic cells,
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α β (VLA-5) and α β (VLA-6) on hematopoietic cells. In combi- including megakaryocytes, platelets, and mast cells. The integ-
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nation with FN in vitro, laminins can expand both HSCs and several rin α β is expressed on monocyte-macrophages and neutrophils and
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more differentiated progenitors. Laminins are composed of α, β, and γ mediates their transendothelial migration. 347,348 The vitronectin receptor
polypeptides with expression of laminin-2 (α β γ ), laminin-8 (α β γ ), cooperates with TSP and CD36 in the recognition and phagocytosis of
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