Pathology

Increased BM blood flow has been described in cases of increased hematopoietic demand such as that observed in hemolytic anemia, which is in agreement with experimental data on animals after bleeding. Similarly, some authors have related the bone pain experienced by patients administered with G-CSF to the increased blood flow associated to an increase in the interstitial fluid pressure in the BM.

The myeloproliferative syndrome associates neoplastic blood cell diseases (polycythemia vera, chronic myeloge-nous leukemia, myelofibrosis) affecting HSCs and resulting in overproduction of blood cells, fibrosis of the hematopoi-etic parenchyma, and reactivation of liver and spleen hematopoiesis. In this syndrome the BM blood flow is increased. In myelofibrosis there is novel vessel formation (angiogenesis).

Angiogenesis is also a major anatomo-pathological feature of acute leukemias and multiple myeloma. Neoplastic cells (leukemic blasts or plasma cells), by producing angiogenic factors -cytokines such as fibroblast growth factor-2 (FGF-2) or vascular endothelial growth factor (VEGF) and/or metalloproteases (MMP2, MMP9), induce endothe-lial cell proliferation and organization into capillary tubes that provide oxygen and help tumor development.

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Figure 1 Molecular modeling of HSC trafficking. Data supporting the following models are provided mainly by studies in vitro using HSCs, BM ECs, and stromal cells generated from long-term marrow cultures. (A) HSC homing. (1) Weak interactions between P-selectin glycoprotein ligand-1 (PSGL-1) expressed on HSCs and E-and P-selectins constitutively expressed on BM ECs lead HSCs to tether to, and roll along, the BM endothelium. SDF-1 located on the endothelial surface and bound to heparan sulfates induces activation of HSC integrins VLA-4 and LFA-1. VLA-4 and LFA-1 activation converts to firm adhesion their interactions with VCAM-1 and ICAM-1 constitutively expressed on endothelial cells. (2) This activation induces the arrest of HSCs and stimulates actin polymerization that favors HSC transendothelial migration mediated by VLA-4 and VLA-5 in the presence of fibronectin (Fn). (3) HSCs polarize, migrate along the local gradient of SDF-1 produced by stromal cells, and reach the hematopoietic niche. This anchoring depends mainly on close interactions of HSC VLA-4 with stromal cell VCAM-1 and of HSC VLA-5 with Fn of the ECM. Moreover, the continuous production of SDF-1 by stromal cells allows the confinement of HSC within the hematopoietic niche. (B) HSC mobilization. (1) Addition of G-CSF induces (2) a local production of proteases (MMPs, elastases, and cathepsin G). (3) These molecules are able to degrade the ECM. Moreover, elastase can cleave VLA-4/VCAM-1 and (4) CXCR-4/SDF-1 interactions by degrading both CXCR-4 and SDF-1. The loss of attachment to stromal cells and to the ECM together with the loss of SDF-1 activity (5) favors the release of HSCs from the hematopoietic niche. (see color insert)

Angiogenesis is characteristic of diseased BM since in normal conditions there is little, if any, novel vessel formation. Antiangiogenic compounds are therefore promising novel therapeutics for leukemias.

Glossary

Cell adhesion molecules (CAMs): These molecules, expressed on the cell membrane, are involved in cell-to-cell and cell-to-extracellular matrix interactions. They include integrins (e.g., VLA-4 and VLA-5), selectins (e.g., P-, E-, and L-selectins), sialomucins (e.g., CD34 antigen), and immunoglobulin superfamily molecules (e.g.,VCAM-1 and ICAM-1). Interactions between selectins and sialomucins are of low affinity while integrin activation transforms interactions between integrins and immunoglobulin superfamily molecules into the high-affinity state. Integrins can be transiently activated by growth factors, such as c-Kit- and Flt3-ligands and thrombopoietin, or by chemokines, such as SDF-1 and IL-8. This induces changes in the cytoskeleton structure that affects cell motility.

Chemokines: Chemotactic cytokines with low molecular mass (8 to 17kDa) showing approximately 20 to 50 percent sequence homology among each other at the protein level. These molecules mainly exert a chemotactic activity on leukocyte subpopulations induced during inflammatory reactions. They are divided into four groups (CXC, CX3C, CC, and C) according to the positioning of the first two closely paired and highly conserved cysteines of the amino acid sequence. Chemokine receptors belong to the large group of G-protein-coupled seven-transmembrane-domain receptors.

Hematopoiesis: The process of blood cell formation. Blood cells derive from hematopoietic stem cells (HSCs) that are multipotent: They give rise to cells of all blood lineages, and that self-renew. In the progeny of a mother HSC there is a daughter HSC with identical capacity for proliferation and differentiation. HSCs give rise to hematopoietic progenitors with great proliferative potential but that are unable to self-renew, being already committed to a hematopoietic lineage, in turn giving rise to precursors (differentiating cells). The process is extremely dynamic since several billion hematopoietic cells need to be generated from a small compartment of HSCs each day to replace dying blood cells.

Microenvironment: The set of nonhematopoietic cells found in the BM parenchyma (cells from the vasculature, fat cells, and endosteal cells). Cells from this compartment derive from a specific population of mesenchymal stem cells (MSCs). One finds therefore in the BM parenchyma two different types of stem cells: HSCs giving rise to blood cells and MSCs giving rise to microenvironmental cells. In long-term marrow cultures hematopoiesis can be maintained for several weeks to months, provided there is generation of adherent stromal cells, therefore considered to be the population associated to HSCs and critical for their maintenance. A subset of stromal cells forms the hematopoietic niche where HSCs in physical contact with stromal cells maintain the adequate balance between self-renewal and differentiation. In vivo, the BM counterpart for stromal cells appears to be a subpopulation of microenvironmental cells with vascular smooth muscle cell characteristics.

Migration: A fundamental process in cell biology that allows cell locomotion. This property is essential during development, particularly embryogenesis, but also throughout adult life. It is a mandatory process for cell renewal such as occurs in hematopoiesis. Two classical types of migration are known: chemotaxis, where cell migration is directed by concentration gradients of soluble extracellular agents, and chemokinesis, characterized essentially by an undirected movement of cells. The main molecular factors involved in the migration process are cell adhesion molecules, chemotactic factors such as chemokines, and proteases, particularly matrix metalloproteinases (MMPs).

Further Reading

Charbord, P., Tavian, M., Humeau, L., and Peault, B. (1996). Early ontogeny of the human marrow from long bones: An immunohisto-

chemical study of hematopoiesis and its microenvironment. Blood 87, 4109-4119.

Dennis, J. E., and Charbord, P. (2002). Origin and differentiation of human and murine stroma. Stem Cells 20, 205-214. A review on the hematopoietic microenvironment. Iversen, P. O., Nicolaysen, G., and Benestad, H. B. (1993) The leukopoietic cytokine granulocyte colony-stimulating factor increases blood flow to rat bone marrow. Exp. Hematol. 21, 231-235. Levesque, J. P., Takamatsu, Y., Nilsson, S. K., Haylock, D. N., and Simmons, P. J. (2001). Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 98, 1289-1297. Lichtman, M. A. (1981) The ultrastructure of the hemopoietic environment of the marrow: A review. Exp. Hematol. 9, 391-410. Peled, A., Petit, I., Kollet, O., Magid, M., Ponomaryov, T., Byk, T., Nagler, A., Ben-Hur, H., Many, A., Shultz, L., Lider, O., Alon, R., Zipori, D., and Lapidot, T. (1999). Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283, 845-848. This paper provides strong evidence for the pivotal role of CXCR-4/SDF-1 interaction for HSC homing into the bone marrow. Models of in vitro migration along a SDF-1 gradient and of engraft-ment in mice were used. Both migration and homing of HSCs were prevented by antibodies blocking SDF-1 or downregulation of CXCR-4, but increased by CXCR-4 upregulation. Peled, A., Kollet, O., Ponomaryov, T., Petit, I., Franitza, S., Grabovsky, V., Slav, M. M., Nagler, A., Lider, O., Alon, R., Zipori, D., and Lapidot, T. (2000). The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: Role in transendothe-lial/stromal migration and engraftment of NOD/SCID mice. Blood 95, 3289-3296.

Perez-Atayde, A. R., Sallan, S. E., Tedrow, U., Connors, S., Allred, E., and Folkman, J. (1997). Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am. J. Pathol. 150, 815-821. A princeps paper showing the involvement of angiogenesis in a neoplastic blood disease. Petit, I., Szyper-Kravitz, M., Nagler, A., Lahav, M., Peled, A., Habler, L., Ponomaryov, T., Taichman, R. S., Arenzana-Seisdedos, F., Fujii, N., Sandbank, J., Zipori, D., and Lapidot, T. (2002). G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat. Immunol. 3, 687-694. G-CSF-induced HSC mobilization leads to a dramatic decrease of marrow SDF-1 levels in mice. This phenomenon is related to local proteolytic degradation of SDF-1 by neutrophil elastase and is correlated to HSC mobilization. Antibodies neutralizing CXCR-4 and SDF-1 inhibited human and murine HSC mobilization, demonstrating the role of SDF-1/CXCR-4 signaling in cell egress.

Weiss, L., and Geduldig, U. (1991) Barrier cells: Stromal regulation of hematopoiesis and blood cell release in normal and stressed murine bone marrow. Blood 78, 975-990.

Capsule Biography

Dr. Jorge Domenech is a university scientist and physician with clinical and experimental experience in hematopoiesis. His research is focused on the mechanisms leading to the migration of hematopoietic stem cells.

Dr. Pierre Charbord is an Inserm scientist with experience in experimental hematology. His research is focused on the hematopoietic microenvironment (stromal and hematopoietic stem cells).

Section E

Kidney

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