A critical role of VLA-4 in erythropoiesis in vivo

Abstract

Hematopoiesis requires specific interactions with the microenvironments, and VLA-4 has been implicated in these interactions based on in vitro studies. To study the role of VLA-4 in hematopoiesis in vivo, we performed in utero treatment of mice with an anti-VLA-4 monoclonal antibody. Although all hematopoietic cells in fetal liver expressed VLA-4, the treatment specifically induced anemia. It had no effect on the development of nonerythroid lineage cells, including lymphoids and myeloids. In the treated liver almost no erythroblast was detected, whereas the erythroid progenitors, which give rise to erythroid colonies in vitro, were present. These results indicate that VLA-4 plays a critical role in erythropoiesis, while it is not critical in lymphopoiesis in vivo.

Erythrocytic precursor cells show potent shear stress resistant adhesion and home to hematopoietic tissue in vivo

“…A model has been proposed where, during their maturation, erythrocytic precursors migrate from erythropoietic islands to the sinusoids, and from there, they are released as enucleated reticulocytes into the circulation 11,17 . The adhesion potential of these precursors has been shown to decrease proportionally with their maturation 13,14,18,19 . This corresponds to our observations gathered from the shear stress adhesion studies on the ligand of VLA‐4, VCAM‐1.…”

“…The physiologic formation of RBCs from their precursors occurs in erythroblastic islands within the marrow, which consist of a central macrophage surrounded by maturating erythroblasts 9‐11 . The interaction of maturating erythrocytic cells with marrow stromal cells involves binding between the integrin VLA‐4 and specific domains of fibronectin 11‐16 . A model has been proposed where, during their maturation, erythrocytic precursors migrate from erythropoietic islands to the sinusoids, and from there, they are released as enucleated reticulocytes into the circulation 11,17 .…”

Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an α4 integrin inhibitor

“…The results of a study in mice suggest that α4β1 integrin has an important role in hematopoiesis in murine fetal liver. For example, a monoclonal antibody against murine VLA‐4 administered to mouse dams at∼40 mg/kg/day (similar to the high dose in this study) from GD 7 to term resulted in marked anemia (RBC counts 1/5 of controls), a severe decrease in hepatic erythroblasts, and a reduction in fetal erythroid progenitor cells in the neonates (Hamamura et al, 1996). Our findings of anemia in the fetuses of dams treated with natalizumab are consistent with the observations of Hamamura et al, although anemia is less severe in the monkeys than in the mice.…”

Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice

“…Fibronectin mutants die early at E10 prior to fetal liver development, thus precluding analysis of definitive erythropoiesis. Moreover, an important role for VLA-4, a known fibronectin receptor, has also been shown to play an important role for erythropoiesis in vivo (Hamamura et al, 1996).…”