Changes in integrin expression are associated with altered homing properties of Lin-/loThy1.1loSca-1+ +c-kit+ hematopoietic stem cells following mobilization by cyclophosphamide/granulocyte colony-stimulating factor

Objective. Although migration of hematopoietic stem cells (HSC) is essential for normal hematopoiesis and successful hematopoietic cell transplantation, little is known about the mechanisms that underlie this movement. We have sought to characterize the factors that regulate HSC migration by analyzing changes in expression of particular adhesion receptors associated with c cylophosphamide/granulocyte colony-stimulating factor (Cy/G-CSF)-induced HSC mobilization. Methods. Expression by Lineage -/(lo)Thy1.1(lo)Sca-1(+)-c-kit HSC of members of the beta1 integrin family of adhesion molecules was assessed in untreated or Cy/G-CSF-treated mice by multi-parameter flow cytometry. In parallel, the in vivo homing properties of normal and mobilized HSC were compared following intravenous transfer of fluorescently marked HSC. Results. Normal adult HSC express high levels of several beta1 integrin family members. Following Cy/G treatment, bone marrow HSC selectively. downregulate A integrin expression and upregulate alpha5 expression. HSC found in the blood following Cy/G-CSF treatment express significantly lower levels of multiple integrins than their bone marrow and/or splenic counterparts. Changes in integrin expression by blood-borne HSC correlate with a 50% decrease in their ability to home to the bone marrow in short-term assay's, and Both previously observed defects in competitive engraftment by these HSC. Similar reductions in bone marrow (BM) homing are observed for BM HSC treated with alpha4 integrin function blocking mAb prior to injection. Modulation or integrin expression induced by mobilization was not associated with cell-cycle progression. Conclusion. Changes in integrin expression and function are associated with HSC mobilization and likely significantly, affect the engraftment potential of hematopoietic stem cells. (C) 2002 International Society for Experimental Hematology. Published by, Elsevier Science Inc.