Differential role for very late antigen-5 in mobilization and homing of hematopoietic stem cells

Abstract

The role of very late antigen-5 (VLA-5) in homing and mobilization of hematopoietic stem cells from normal bone marrow (NBM) and bone marrow (MBM) and peripheral blood (MPB) from mobilized mice was investigated. We found a decreased number of VLA-5-expressing cells in the lineage-negative fraction of MPB. However, virtually all stem/progenitor cells were present in the VLA-5 þ fraction and hence mobilization of hematopoietic stem cell subsets does not coincide with a downregulation of VLA-5. Stem/progenitor cells from MPB and MBM demonstrated enhanced stromal-derived factor-alpha-induced migration. This enhanced migration correlates with an improved hematopoietic reconstitution potential, with the migrated MPB cells showing the fastest reconstitution. Interestingly, homing of MPB, MBM and NBM stem/progenitor cells in bone marrow and spleen did not differ and is therefore not responsible for the differences in hematopoietic reconstitution. The observed increase in VLA-5 þ cells in the recipients after transplantation can most probably be attributed to selective homing of VLA-5 þ cells instead of an upregulation of VLA-5. Treatment with an antibody to VLA-5 partially inhibited bone marrow homing of progenitor cells, whereas homing in the spleen was hardly affected. These data indicate a differential role for VLA-5 in the movement of stem cells from and toward bone marrow.

Combinatorial and distinct roles of α5 and α4 integrins in stress erythropoiesis in mice

“…23 Consistent with this concept, previous data with fetal liver ␤ 1 knockout cells have shown failure of BM and splenic colonization by fetal liver ␤ 1 null cells 45 ; and in another study, there was a small decrease in homing to irradiated spleen with anti-␣ 5 integrin antibody-treated donor cells. 15 However, our present data, showing no significant impairment of splenic homing in nonirradiated recipients given adult ablated ␤ 1 cells ( Figure 5; supplemental Figure 1), appear inconsistent with these data. In this context, it is important to emphasize that homing in some of the previous data was evaluated by successful engraftment (colonization), whereas in our studies we have dissociated homing/lodgment events from subsequent expansion/engraftment events with ␤ 1 ⌬/⌬ cells.…”

“…Both ␣ 4 and ␣ 5 integrins are widely expressed in hematopoietic cells and have been implicated in several functional aspects, such as proliferation, survival, maturation of erythroid cells, or in homing and proliferation of hematopoietic progenitor cells. [9][10][11][12][13][14][15] However, in vitro and in vivo data have not been consistent, so that the exact role of these 2 integrins has remained inconclusive. For example, adhesion to fibronectin is dependent on both ␣ 4 ␤ 1 and ␣ 5 ␤ 1 , and it was found to influence stem cell homing of hematopoietic progenitors to BM or spleen, but the results have been controversial for ␣ 5 integrin.…”

The Endoplasmic Reticulum Chaperone Protein GRP94 Is Required for Maintaining Hematopoietic Stem Cell Interactions with the Adult Bone Marrow Niche

“…To investigate the potential mechanism by which GRP94 maintains the interaction between HSCs and the niche, we examined the cell surface expression of integrin α4 and α5, which are known to be important for the homing and adhesion of HSCs to the endosteal niche [49], [50]. Flow cytometric analysis with mouse BM LSKFlk2 − and LSKFlk2 + populations demonstrated significantly lower expression of cell surface CD49d (integrin α4/β1) on cKO than WT cells, whereas CD49e (integrin α5/β1) expression was comparable between the two groups (Figure 10A).…”

Protein kinase B (PKB/c-akt) regulates homing of hematopoietic progenitors through modulation of their adhesive and migratory properties

“…Finally, HSCs anchor to their specialized niches within the bone marrow compartment near osteoblasts and initiate long-term repopulation. Adhesion molecules [7][8][9][10][11] have been shown to be involved in homing of HSCs.…”