The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice.
Hematopoietic stem cell homing and engraftment require several adhesion interactions, which are not fully understood. Engraftment of nonobese/severe combined immunodeficiency (NOD/SCID) mice by human stem cells is dependent on the major integrins very late activation antigen-4 (VLA-4); VLA-5; and to a lesser degree, lymphocyte function associated antigen-1 (LFA-1). Treatment of human CD34(+) cells with antibodies to either VLA-4 or VLA-5 prevented engraftment, and treatment with anti-LFA-1 antibodies significantly reduced the levels of engraftment. Activation of CD34(+) cells, which bear the chemokine receptor CXCR4, with stromal derived factor 1 (SDF-1) led to firm adhesion and transendothelial migration, which was dependent on LFA-1/ICAM-1 (intracellular adhesion molecule-1) and VLA-4/VCAM-1 (vascular adhesion molecule-1). Furthermore, SDF-1-induced polarization and extravasation of CD34(+)/CXCR4(+) cells through the extracellular matrix underlining the endothelium was dependent on both VLA-4 and VLA-5. Our results demonstrate that repopulating human stem cells functionally express LFA-1, VLA-4, and VLA-5. Furthermore, this study implies a novel approach to further advance clinical transplantation.
Peled
A
A
Departments of Immunology and Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Kollet
O
O
Ponomaryov
T
T
Petit
I
I
Franitza
S
S
Grabovsky
V
V
Slav
M M
MM
Nagler
A
A
Lider
O
O
Alon
R
R
Zipori
D
D
Lapidot
T
T
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018952:Antigens, CD34; D002448:Cell Adhesion; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis; D004730:Endothelium, Vascular / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000502:physiology; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D017469:Receptors, Fibronectin / Q000037:antagonists & inhibitors / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors / Q000502:physiology*; D017154:Stromal Cells / Q000502:physiology*; D014183:Transplantation, Heterologous / Q000276:immunology*
D000906:Antibodies; D018952:Antigens, CD34; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing