Page 2081 - Hematology_ Basic Principles and Practice ( PDFDrive )

1850 Part XII Hemostasis and Thrombosis

Remodeling of a preexisting collateral arteriole is thought to be Significant evidence now indicates that hematopoietic stem and
caused by flow-induced changes secondary to occlusion of a supply progenitor cells are not randomly distributed in the BM, but rather
artery. The consequent increase in shear stress through the collateral are spatially and possibly physically associated with the endosteum
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arteriole activates endothelial cells, resulting in monocyte recruitment and the blood vessels. Functional differences between the osteo-
and infiltration into the media. Elaboration of various cytokines, blastic and vascular niches have been described. It has been suggested
growth factors, and proteases from monocytes and endothelial cells that whereas the osteoblastic niche maintains quiescence of HSCs,
causes matrix degradation, smooth muscle cell proliferation, and stem and progenitor cells that are activated for differentiation and
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rapid enlargement of the preexisting arteriole. Factors thought to mobilization reside at the vascular niche. Translocation of mega-
promote arteriogenesis include FGF-2, placental growth factor, karyocyte progenitors to the vicinity of the BM sinuses is sufficient
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PDGF-BB, TGFβ1, monocyte chemoattractant protein 1, and to induce megakaryocyte maturation and platelet production.
GM-CSF. 185,186 However, a study has identified CXCL12 (SDF-1)–abundant reticu-
lar cells that are located in close proximity to the sinusoidal endothe-
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lium as well as the endosteum. The authors confirmed that the
Lymphangiogenesis CXCL12–CXCR4 signaling axis is required for maintenance of
HSCs in the BM, and these findings raise the possibility that the
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The lymphatics comprise a low-flow, low-pressure system that collects vascular and osteoblastic niches may not be that different. In all
extravasated fluid from the tissues and transfers it back to the venous likelihood, endothelial cells and osteoblasts, in concert with other
system via the thoracic duct. Lymphatic vessels also serve an immune stromal cells, provide a finely tuned system to modulate hematopoi-
function by transporting lymphoid and antigen-presenting cells to esis in the BM such that differentiation, proliferation, and self-renewal
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lymphoid organs. Lymphatic vessels share features with blood occur in a regulated fashion.
vessels, but they also exhibit differences. Lymphatic vessels develop Human endothelial cells have been reported to express receptors
shortly after blood vessels and may arise de novo from precursor for IL-3, stem cell factor, erythropoietin, and thrombopoietin, and
mesenchymal cells (lymphangioblasts) in a process akin to vasculo- show functional responses to IL-3 and erythropoietin. 199–201 The
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genesis. Alternatively, other studies suggest that specific venous shared responses to growth factors, combined with the importance
endothelial cells differentiate to lymphatic endothelium in response of macrophages in angiogenesis and the production of cytokines by
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to signals that have yet to be determined. VEGF-C and VEGF-D, monocytes and macrophages, suggest that hematopoietic cells play a
by activating VEGFR-3 and Ang2 potentially through Tie2 activa- reciprocal role in maintaining the endothelium.
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tion, are growth factors necessary for lymphatic vessels. The α9β1
integrin and matrix interacting protein CCBE1 are necessary for
proper lymphatic development, and the homeobox transcription PHYSIOLOGIC FUNCTIONS OF THE ENDOTHELIUM
factor Prox1 appears to induce transdifferentiation of venous to
lymphatic endothelial cells. 189–191 The earliest described regulator of The Endothelium as a Barrier
early lymphatic endothelial cell specification is Sox18 (sex determin-
ing Region Y Box 18), a transcriptional regulator of Prox1expression. The microvessels (capillaries and postcapillary venules) act as the
Lymphedema can be caused by congenital defects, parasitic (filariasis) exchange vessels of the circulation. However, as with other endothelial
or neoplastic obstruction, or surgical resection. Congenital lymph- functions, vessel permeability is dependent on the type of vessel and
edema (Milroy disease) is linked to inactivating mutations of its location. Movement of lipophilic and low-molecular-weight
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VEGFR-3. Whether lymphatic vessel density in human tumors hydrophilic substances between blood and tissue is virtually unim-
correlates with disease progression is not clear, but in animal models, peded, but the vessels are selectively permeable to macromolecules.
induction of lymphangiogenesis by VEGF-C or VEGF-D promotes This semiselective barrier is necessary to maintain the fluid balance
lymph node metastasis. 187 between intravascular and extravascular compartments, yet antibod-
ies, hormones, cytokines, and other molecules must have access to
Relationship Between Vascular Development and the interstitial space for the initiation and potentiation of various
processes, including inflammation, immune response, and wound
Hematopoiesis repair.
Movement of macromolecules across the vessel wall is governed
Hematopoietic cells and endothelial cells are intertwined in several by (1) hydrostatic and oncotic pressure gradients; (2) physicochemi-
ways. First, there is the likely existence of a common precursor (see cal properties of the molecule, such as size, shape, and charge; and
Vasculogenesis section earlier). Second, the endothelium is intimately (3) properties of the barrier. The barrier of the vessel wall is formed
involved in hematopoiesis, having a supportive role structurally and by the cellular components, endothelial cells, and pericytes, as well
nutritionally. Finally, the endothelium organizes the controlled egress as by the charge and compactness of the matrix components, glycoca-
and ingress of hematopoietic cells in hematopoietic and other tissues. lyx, and basement membrane. Macromolecules can pass either
The last issue is covered in the Interaction of Blood Cells With the directly through the endothelial cell (transcellular path) or between
Vessel Wall section. adjacent endothelial cells (paracellular path). Surprisingly, the mecha-
BM stromal cells secrete cytokines, produce ECM, and are in nisms of macromolecular movement remain controversial, and data
direct cellular contact with hematopoietic cells, thereby providing a generated by physiologists, morphologists, and cell biologists have
microenvironment suitable for hematopoietic proliferation, differen- not been consolidated into a model that satisfies the findings of the
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tiation, and self-renewal. Many studies demonstrate the supportive different groups. 202
role of endothelium in hematopoiesis. 193–195 The physical proximity To explain cellular transport in endothelium, physiologists have
of endothelium and hematopoietic precursors within the BM and the proposed the existence of two sets of “pores” based on experiments
requirement of blood cells to transit BM endothelium to reach the measuring the movement of dextran and other macromolecules:
circulation is presumptive evidence of an important role for endothe- a small pore of radius 3–5 nm for transport of water and small
lium. BM endothelial cells constitutively express high levels of IL-6, hydrophilic molecules, and a large pore of radius 25–60 nm for
stem cell factor, granulocyte colony-stimulating factor (G-CSF), and macromolecular transport. 202–204 Although water mainly moves across
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granulocyte macrophage colony-stimulating factor (GM-CSF). the continuous endothelium via the paracellular route, a significant
Both yolk sac and BM endothelial cells support long-term prolifera- proportion (≤40%) can traverse the endothelium via the transcellular
205
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tion and differentiation of hematopoietic cells in vitro. BM route by water-transporting membrane channels, the aquaporins.
endothelial cell expression of notch ligand jagged supports long-term Macromolecular transport into cells can proceed by receptor-mediated
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notch-dependent HSC proliferation and renewal. However, endo- systems, such as clathrin-coated pits, in which the molecules usually
thelial cells also have been reported to inhibit hematopoiesis. 197 are targeted to the lysosome, but may be transported through