Flt3‐ligand induces adhesion of haematopoietic progenitor cells via a very late antigen (VLA)‐4‐ and VLA‐5‐dependent mechanism

Abstract

Summary. The adhesion of haematopoietic progenitor cells (HPC) to the bone marrow microenvironment is a process regulated by cytokines. In this study, we have shown that flt3-ligand (FL), a growth factor that controls early haematopoiesis, regulated the function and expression of the beta-1 integrins, very late antigen (VLA)-4 and VLA-5 on HPC. The modulation of the adhesiveness of HPC by FL was studied by adhesion assays on umbilical vein endothelial cells (HUVEC). Stimulation by FL induced two peaks of increased adhesiveness of HPC. The first peak was at around 30 min and was mechanistically related to an activation of the beta-1 integrins, mainly VLA-4 and VLA-5. The second peak was at around 12 h and was related to increased expression of VLA-4 and VLA-5. The control of HPC adhesiveness by FL is a previously unreported property of FL that may be important for the homing and the retention of flt3-expressing HPC within the bone marrow microenvironment.

Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia

“…It is also possible that there may be alternative downstream signaling pathways for VLA-4, analogous to the distinct pathways induced by the Flt3 tyrosine kinase domain mutations as opposed to the Flt3-ITDs. 31 Moreover, there are countless other potentially contributing influences; for example, Flt3 ligand itself has been shown to enhance adhesion via VLA-4, 32 and Flt3-ITDs may enhance the expression of CXCR-4, involved in marrow homing/retention through binding of SDF-1, and thought to convey poor prognosis in AML. [33][34][35] These data suggest that sVCAM-1 binding by AML blasts may have value as a prognostic parameter for OS at diagnosis.…”

Integrin Profile and In Vivo Homing of Human Smooth Muscle Progenitor Cells

“…1 Integrins are known to play a key role in mediating anchorage between progenitor and vascular cells and ECM, potentiating cell differentiation, cell migration, and proliferation. 4,10 In vitro matrix models suggest different vascular cells share several integrins with potentially overlapping matrix-binding characteristics, and indeed, the constituents of the matrix environment are a strong determinant of specific integrin interaction.…”

“…3 The second group comprises heterodimeric surface adhesion molecules (integrins) known to support physical association between circulating progenitor cells and vascular extracellular matrix (ECM). 4 Recently, we described the existence of SPCs in human peripheral blood 5 and have also shown that bone marrowderived smooth muscle cells are highly enriched in the intima of human atherosclerotic vessels. 6 Understanding the homing, adhesion, and recruitment characteristics of SPCs may have significant implications for understanding basic mechanisms of atherogenesis and for development of novel therapeutics to treat vascular disease.…”

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

“…SCF has been shown to improve homing capacity of UCB cells in preclinical models. 53 FL leads to short-term expansion 54,55 and helps regulate 56 the expression of very late antigen (VLA)-4 and VLA-5, adhesion molecules which play a part in proliferation and differentiation either directly or through the modulation of cytokineinduced signals. 57,58 In a study to evaluate cytokine combinations that lead to expansion without change in repopulating potential, Levac et al 59 cultured CD34 þ CD38ÀLinÀ cord blood cells in serum-free media with SCF and FL and found that TPO may be able to replace IL-3, IL-6 and G-CSF without changing the number of SRC.…”