Vascular cell adhesion molecule-1 expressed by bone marrow stromal cells mediates the binding of hematopoietic progenitor cells.
Human bone marrow-derived CD34+ cells were analyzed for the expression of the beta 1-family of integrin adhesion molecules. Integrin alpha 4 beta 1 was consistently expressed by greater than 90% of CD34+ cells, including essentially all assayable granulocyte-macrophage colony-forming cells (CFU-GM) and erythroid bursts (BFU-E) as shown by fluorescence-activated cell sorting studies. Adhesion of highly enriched CD34+ cells to cultured allogeneic marrow stromal cells was largely inhibited both by monoclonal antibody to alpha 4 beta 1 and to vascular cell adhesion molecule-1 (VCAM-1), a ligand for alpha 4 beta 1. VCAM-1 was found to be expressed by bone marrow stromal elements in vitro both constitutively at low level and at high levels after treatment with cytokines. Induction of VCAM-1 was cytokine- and time-dependent with maximum levels being obtained after 4 hours of exposure to a combination of interleukin-4 and tumor necrosis factor-alpha. Cytokine-induced stromal cells bound threefold higher numbers of CFU-GM and BFU-E, this increase being abrogated by anti-alpha 4 beta 1 and anti-VCAM-1 antibodies. In addition, the adhesion to stroma of more immature progenitors, the long-term culture initiating cells, also occurred through an alpha 4 beta 1/VCAM-1-dependent mechanism. These studies identify an adhesion mechanism of potential importance in the localization of primitive progenitors within the hematopoietic microenvironment.
Simmons
P J
PJ
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA.
Masinovsky
B
B
Longenecker
B M
BM
Berenson
R
R
Torok-Storb
B
B
Gallatin
W M
WM
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000032:analysis*; D018952:Antigens, CD34; D001853:Bone Marrow / Q000502:physiology*; D001854:Bone Marrow Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000502:physiology*; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000032:analysis; D007700:Kinetics; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018952:Antigens, CD34; D015815:Cell Adhesion Molecules; D016023:Integrins; D019010:Vascular Cell Adhesion Molecule-1