Signals from platelet/endothelial cell adhesion molecule enhance the adhesive activity of the very late antigen-4 integrin of human CD34+ hemopoietic progenitor cells.
Adhesive interactions between human CD34+ hemopoietic progenitor cells and bone marrow stromal cells control the localization, proliferation, and differentiation of CD34+ cells. Changes in adhesive interactions may contribute to the mobilization of CD34+ cells to the blood induced by chemotherapy and cytokines. Thus, the identities and functional states of adhesion receptors are critical properties of CD34+ cells. Here, we confirm that the adhesion receptors very late antigen-4 (VLA-4), LFA-1, and platelet/endothelial cell adhesion molecule-1 (PECAM-1) are expressed on the CD34+ cell line KG1a and on CD34+ normal, steady state bone marrow cells. Therapeutically mobilized CD34+ cells express similar levels of PECAM-1 but reduced levels of VLA-4 and LFA-1 in comparison with steady state bone marrow cells. Integrin adhesive activity was measured from the binding of PKH 26- or phycoerythrin-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 were analyzed by flow cytometry for the loss of free CD34+ cells and gain of CD34(+)-CHO cell aggregates. VLA-4 mediates the strong and specific adhesion of KG1a cells and bone marrow CD34+ cells to VCAM-1-transfected CHO cells. CD34+ cells mobilized with granulocyte colony stimulating 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 enhanced by Abs to the coexpressed adhesion receptor PECAM-1, implicating signals transmitted from PECAM-1 as determinants of VLA-4 integrin activity. VLA-4 function in CD34+ cells mobilized with G-CSF or cyclophosphamide is equivalent to steady state CD34+ cells. LFA-1 mediates minimal adhesion between CD34+ cells and intercellular CAM-1 transfected CHO cells and is refractory to PECAM-1 modulation. We infer that VLA-4, but not LFA-1, contributes to the constitutive adhesive phenotype of CD34+ cells. PECAM-1 is probably one of several receptors that control adhesive interactions between hemopoietic progenitors and target cells by regulating the activation states of specific integrins.
Leavesley
D I
DI
Matthew Roberts Laboratory, Hanson Centre for Cancer Research, Adelaide, Australia.
Oliver
J M
JM
Swart
B W
BW
Berndt
M C
MC
Haylock
D N
DN
Simmons
P J
PJ
D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000502:physiology*; D016466:CHO Cells; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000502:physiology*; D002460:Cell Line; D006224:Cricetinae; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016029:Receptors, Very Late Antigen / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016029:Receptors, Very Late Antigen