Contribution of α6 integrins to hematopoietic stem and progenitor cell homing to bone marrow and collaboration with α4 integrins

Abstract

The laminin receptor integrin ␣6 chain is ubiquitously expressed in human and mouse hematopoietic stem and progenitor cells. We have studied its role for homing of stem and progenitor cells to mouse hematopoietic tissues in vivo. A function-blocking anti-integrin ␣6 antibody significantly reduced progenitor cell homing to bone marrow (BM) of lethally irradiated mice, with a corresponding retention of progenitors in blood. Remarkably, the anti-integrin ␣6 antibody profoundly inhibited BM homing of long-term multilineage engrafting stem cells, studied by competitive repopulation assay and analysis of donor-derived lymphocytes and myeloid cells in blood 16 weeks after transplantation. A similar profound inhibition of long-term stem cell homing was obtained by using a function-blocking antibody against ␣4 integrin, studied in parallel. Furthermore, the anti-integrin ␣6 and ␣4 antibodies synergistically inhibited homing of short-term repopulating stem cells. Intravenous injection of antiintegrin ␣6 antibodies, in contrast to antibodies against ␣4 integrin, did not mobilize progenitors or enhance cytokineinduced mobilization by G-CSF. Our results provide the first evidence for a distinct functional role of integrin ␣6 receptor during hematopoietic stem and progenitor cell homing and collaboration of ␣6 integrin with ␣4 integrin receptors during homing of short-term stem cells. IntroductionHematopoietic stem cell (HSC) properties, like self-renewal, proliferation, differentiation, and migration are critically dependent on the regulatory signals from the surrounding bone marrow (BM) microenvironment. Cytokines, growth factors, stromal cell surface molecules, and extracellular matrix (ECM) molecules contribute to this regulation by binding to distinct cell surface receptors and thereby activating intracellular signal transduction pathways. During steady-state hematopoiesis, small numbers of HSCs are circulating in blood, indicating that their continuous mobilization into blood and homing into BM is a physiologic process. 1 For clinical stem cell transplantation, HSCs are mobilized from BM by injection of growth factors and can be harvested from blood. After transplantation, HSCs selectively transmigrate through the sinusoidal walls into the BM extravascular spaces to engraft and reconstitute hematopoiesis. In leukemias, cell proliferation, differentiation, and migration are dysregulated, and consequently high numbers of immature malignant cells are released into blood and accumulate in the BM, and aberrantly in other tissues.The molecular mechanisms involved in HSC homing and mobilization have been widely studied, but are still not fully understood. 2,3 They are apparently multistep processes involving chemokines, growth factors, matrix-degrading enzymes, and cell adhesive interactions mediated by specific receptors on hematopoietic cells. Members of the integrin family of adhesion receptors are widely expressed in the hematopoietic system, and both in vitro and in vivo studies have indicated decisive roles for several ...

The p67 laminin receptor identifies human erythroid progenitor and precursor cells and is functionally important for their bone marrow lodgment

“…1,2,4,6,25 However, a lineage-specific effect was not previously observed. As shown, the laminin-binding receptor p67 is preferentially expressed on human erythroid progenitors and precursors, and its blockade preferentially restricts BM homing/retention of BFU-Es.…”

The integrin 9 1 on hematopoietic stem and progenitor cells: involvement in cell adhesion, proliferation and differentiation

“…[13][14][15] Both α4 and α6 integrins are functionally involved in stem cell homing. 16 Whether the integrin α7-α11 chains are also prominently expressed on the cell surface of human HSPC has not been studied in detail. The present study now provides evidence that the integrin α9β1 is also a cellular receptor directly involved in hematopoietic stem cell functions.…”

Murine allogeneic in vivo stem cell homing,

“…Stromal-derived growth factor 1 and CXCR4 appear to form an especially critical axis for homing of stem cells and along with the VLA-4/VCAM-1 axis play a prominent role in marrow homing. More recently, utilizing a phage display approach, Nowakowski et al (2004) identified CD84 as being a marrow homing protein and the calcium receptor has been proposed to be important in the intra-marrow movement of stem cells to the endosteal niche (Papayannopoulou and Nakamoto, 1993;Papayannopoulou et al, 1995;Simon et al, 1998;Zanjani et al, 1999;Adams et al, 2006;Jung et al, 2006;Qian et al, 2006).…”