The alpha4beta1 and alpha5beta1 integrins mediate engraftment of granulocyte-colony-stimulating factor-mobilized human hematopoietic progenitor cells.
BACKGROUND
The alpha4beta1 and alpha5beta1 integrins are major adhesion molecules of murine and human hematopoietic progenitor cells. Granulocyte-colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPCs) are the most important source for clinical hematopoietic cell transplantation today. The contribution of alpha4beta1 and alpha5beta1 integrins to homing of PBPCs has not been studied yet.


METHODS
The expression of alpha4beta1 and alpha5beta1 integrins on purified human PBPCs was analyzed. Integrin function in adhesion to recombinant fibronectin and migration on fibronectin-coated transwells was assessed with fragments combining different adhesion domains and function-blocking antibodies. Finally, the function of those integrins in a transplantation model was investigated with repopulating cells of nonobese diabetic/severe combined immune-deficient (NOD/SCID) mice.


RESULTS
More than 90 percent of all purified peripheral blood CD34+ cells express alpha4beta1 integrins, whereas only 10 to 15 percent express alpha5beta1. The alpha4beta1 integrin alone influences adhesion whereas alpha4beta1 and alpha5beta1 both mediate chemotaxis of clonogenic CD34+ progenitor cells on recombinant fibronectin. Importantly, antibodies against the integrins alpha4beta1 and alpha5beta1 independently reduce the repopulation of NOD/SCID mouse marrow after transplantation of human peripheral blood CD34+ cells.


CONCLUSIONS
Alpha4beta1 and alpha5beta1 integrins are functional and critical adhesion receptors expressed on G-CSF-mobilized CD34+ hematopoietic blood progenitor cells with repopulating capacity mediating engraftment after transplantation.
Charité, Campus Virchow Klinikum, Institute for Transfusion Medicine, Berlin, Germany.
Dirk
D
Carstanjen
Anna
A
Gross
Nevin
N
Kosova
Iduna
I
Fichtner
Abdulgabar
A
Salama
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D018952:Antigens, CD34 / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D003114:Colony-Forming Units Assay; D005353:Fibronectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D039081:Integrin alpha5beta1 / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008956:Models, Chemical; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D005353:Fibronectins; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor