SIGNALS FROM PLATELET ENDOTHELIAL-CELL ADHESION MOLECULE ENHANCE THE ADHESIVE ACTIVITY OF THE VERY LATE ANTIGEN-4 INTEGRIN OF HUMAN CD34(+)HEMATOPOIETIC PROGENITOR CELLS

Adhesive interactions between human CD34(+) hemopoietic progenitor cel ls and bone marrow stromal cells control the localization, proliferati on, and differentiation of CD34(+) cells. Changes in adhesive interact ions may contribute to the mobilization of CD34(+) cells to the blood induced by chemotherapy and cytokines. Thus, the identities and functi onal states of adhesion receptors are critical properties of CD34(+) c ells. Here, we confirm that the adhesion receptors very late antigen-4 (VLA-4), LFA-1, and platelet/endothelial cell adhesion molecule-1 (PE CAM-1) are expressed on the CD34(+) cell line KG1a and on CD34(+) norm al, steady state bone marrow cells. Therapeutically mobilized CD34(+) cells express similar levels of PECAM-1 but reduced levels of VLA-4 an d LFA-1 in comparison with steady state bone marrow cells. Integrin ad hesive activity was measured from the binding of PKH 26- or phycoeryth rin-labeled CD34(+) cells to FITC-labeled Chinese hamster ovary (CHO) cells expressing vascular CAM-1 (VCAM-1) or intercellular CAM-1, which are ligands for VLA-4 and LFA-1, respectively. Incubation mixtures we re analyzed by flow cytometry for the loss of free CD34(+) cells and g ain of CD34(+)-CHO cell aggregates. VLA-4 mediates the strong and spec ific adhesion of KG1a cells and bone marrow CD34(+) cells to VCAM-1-tr ansfected CHO cells. CD34(+) cells mobilized with granulocyte colony s timulating factor (G-CSF) or cyclophosphamide also bind VCAM-1 via VLA -4. The VLA-4-mediated adhesion of all CD34(+) cells to VCAM-1 is enha nced by Abs to the coexpressed adhesion receptor PECAM-1, implicating signals transmitted from PECAM-1 as determinants of VLA-4 integrin act ivity. VLA-4 function in CD34(+) cells mobilized with G-CSF or cycloph osphamide is equivalent to steady state CD34(+) cells. LFA-1 mediates minimal adhesion between CD34(+) cells and intercellular CAM-1 transfe cted CHO cells and is refractory to PECAM-1 modulation. We infer that VLA-4, but not LFA-1, contributes to the constitutive adhesive phenoty pe of CD34(+) cells. PECAM-1 is probably one of several receptors that control adhesive interactions between hemopoietic progenitors and tar get cells by regulating the activation states of specific integrins.