The α4β1 and α5β1 integrins mediate engraftment of granulocyte-colony- stimulating factor-mobilized human hematopoietic progenitor cells

BACKGROUND: The alpha(4)beta(1) and alpha(5)beta(1) 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 alpha(4)beta(1) and alpha(5)beta(1) integrins to homing of PBPCs has not been studied yet. STUDY DESIGN AND METHODS: The expression of alpha(4)beta(1) and alpha(5)beta(1) 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 alpha(4)beta(1) integrins, whereas only 10 to 15 percent express alpha(5)beta(1). The alpha(4)beta(1) integrin alone influences adhesion whereas alpha(4)beta(1) and alpha(5)beta(1) both mediate chemotaxis of clonogenic CD34+ progenitor cells on recombinant fibronectin. Importantly, antibodies against the integrins alpha(4)beta(1) and alpha(5)beta(1) independently reduce the repopulation of NOD/SCID mouse marrow after transplantation of human peripheral blood CD34+ cells. CONCLUSIONS: A(4)beta(1) and alpha(5)beta(1) integrins are functional and critical adhesion receptors expressed on G-CSF-mobilized CD34+ hematopoietic blood progenitor cells with repopulating capacity mediating engraftment after transplantation.