VLA-4-Mediated Interactions Between Normal Human Hematopoietic Progenitors and Stromal Cells

Abstract

The alpha 4 beta 1 integrin very late activation antigen-4 (VLA-4) has been implicated to play a role in the adhesive interactions between hematopoietic progenitor cells (HPC) and bone marrow stromal cells which express the vascular cell adhesion molecule-1 (VCAM-1) or produce fibronectin (FN). Here, we summarize some of the recent advances made in the elucidation of the role of these particular adhesive interactions for the regulation of normal hematopoiesis. HPC bind to stroma mainly through VLA-4/VCAM-1 interactions. There is evidence which suggests that more primitive HPC constitutively express VLA-4 in a high-affinity state. In vitro studies in the mouse have shown that monoclonal antibodies (mAb) against VLA-4 partly block the development of lymphocytes, myelopoietic cells, and erythropoiesis, whereas in the human system outgrowth of TdT+ B cells is severely retarded by such mAb. In vivo studies revealed that VLA-4 is involved in erythropoietic development, and is particularly important for homing and lodgement of HPC in the bone marrow. Hematopoiesis in mice with deficient expression of alpha 4 integrin or VLA-4's ligand VCAM-1 appears to develop normally. However, chimeras developed from wild-type blastocysts and beta 1 -/- embryonic stem cells do not contain beta 1 -/- hematopoietic cells, although these are present as blood islands in the yolk sac. These beta 1 -/- hematopoietic cells are capable of forming colonies, indicating that beta 1-integrin is not involved in hematopoietic differentiation, but is primarily important for migration of hematopoietic cells into the fetal hematopoietic organs. In addition to the role of VLA-4 in migration, it may also have other regulatory functions. It has been demonstrated that ligation of VLA-4 induces phosphorylation of the protein tyrosine kinase (PTK) pp125FAK as well as other proteins which may be involved in the regulation of ligand affinity. Indeed, it has been shown that tyrosine kinase-dependent stimulation of CD34+ hematopoietic cell lines with c-kit ligand (KL), IL-3 or GM-CSF transiently activates the ability of VLA-4 to bind to VCAM-1 or FN. These events are most probably involved in the induction of quiescence in HPC which adhere to stromal cells. This claim was recently substantiated: when HPC were treated with Fab fragments of an anti-VLA-4 mAb, entry into S-phase of the cell cycle was prevented. Taken together, the present data point to a role for VLA-4 in HPC migration, cell cycle regulation, erythropoiesis and B-lymphopoiesis. Moreover, these insights may explain how defects in adhesive behavior of leukemic HPC through VLA-4 contribute to their dysregulated growth and provide a rationale for therapeutically correcting those defects.

Marrow angiogenesis-associated factors as prognostic biomarkers in patients with acute myelogenous leukaemia

“…Until now, most investigators have attempted to elucidate the impact of a single angiogenic factor on the pathogenesis or prognosis of haematologic malignancies (Aguayo et al, 2002;Litwin et al, 2002;Moehler et al, 2003;Liu et al, 2005;Nowicki et al, 2006). However, HSCs were observed to be in close contact with the marrow stromal cells in vivo (Oostendorp and Dormer, 1997;Tordjman et al, 1999). Furthermore, both fibroblasts and microvascular ECs obtained in normal and leukaemic marrows were reported to produce several angiogenesis molecules (Moehler et al, 2003;De Raeve et al, 2004;Ogawa et al, 2006).…”

Discovery of Very Late Antigen-4 (VLA-4, α4β1 Integrin) Allosteric Antagonists

“…It is expressed on human CD34ϩ cells, and murine HSPCs (31)(32)(33). Blocking the interaction between VLA-4 and its ligands using anti-VLA-4-specific antibodies, or small molecule inhibitors induces mobilization of HSPCs in humans (34,35), primates (36,37), and mice (38).…”

Role of MAdCAM-1 and Its Ligand on the Homing of Transplanted Hematopoietic Cells in Irradiated Mice

“…This regulation appears to be mediated by mutual recognition between adhesion molecules expressed by stromal and vascular endothelial cells (ECs) of hematopoietic tissues and their ligands on HSPCs [26,29,35,37]. Moreover, it is well known that cell adhesion molecules and ligands regulate the migration of HSPCs from the blood stream into the hematopoietic compartment [27].…”