TRANSMIGRATION OF CD34(-FACTORS AND IS MEDIATED BY PECAM-1 (CD31)() CELLS ACROSS SPECIALIZED AND NONSPECIALIZED ENDOTHELIUM REQUIRES PRIOR ACTIVATION BY GROWTH)

The transmigration of hematopoietic progenitor cells (HPCs) across vas cular endothelium is a critical step in the homing of transplanted ste m cells, but the molecular basis for this is unknown. We used mobilize d peripheral blood CD34(+) selected cells and cultured bone marrow mic rovascular (BMECs) and human umbilical vein endothelial cells (HUVECs) to investigate the adhesion and transendothelial migration of HPCs. C olony-forming cells (CFCs) in freshly isolated CD34(+) cells showed hi gh levels of adhesion to both forms of endothelium (28% +/- 4% and 38% +/- 6% of granulocyte-macrophage colony-forming cells [GM-CFCs] adher ing to HUVECs and BMECs, respectively), but were unable to migrate to any significant extent across either (1.0% +/- 0.3% and 1.1% +/- 0.6% of GM-CFCs migrating across HUVECs and BMECs, respectively). Greater t han 95% of peripheral blood CD34(+) cells are in G(0)/G(1) of the cell cycle, but after 48 to 72 hours of stimulation with growth factors (i nterleukin-3 [IL-3] 12 ng/mL, stem cell factor 10 ng/mL, and IL-6 10 n g/mL), 28% +/- 5% of cells were in S+G(2)/M. Growth factor stimulation had no effect on the adhesion of mobilized CFCs but resulted in enhan ced migration of these cells (9.8% +/- 1.6% and 12.6% +/- 3.1% of GM-C FCs migrating across HUVECs and BMECs, respectively; P < .01, n = 6). Assessment of cell proliferation by the H-3-thymidine suicide method s howed that, whereas 11.7% +/- 3.3% of proliferating CFCs transmigrated across endothelium, only 1.3% +/- 0.3% of nonproliferating CFCs did s o (P < .05, n = 5). Transmigration of growth factor-activated CFCs was inhibited by anti-CD18 monoclonal antibody (MoAb; 50% +/- 18% inhibit ion) and by anti-platelet endothelial cell adhesion molecule-1 (PECAM- 1) MoAb (70.8% +/- 7.1% inhibition; P < .05, n = 3). IL-1 stimulation of HUVECs had no significant effect on CD34(+) cell transmigration, bu t caused marked enhancement of neutrophil migration. Stem cell homing may depend, in part, on the ability of local cytokines to upregulate t he transmigratory ability of these cells. The transmigration of HPCs s hares at least some molecular pathways with that of mature cells (CD18 and PECAM-1), but is differently affected by endothelial activation. (C) 1998 by The American Society of Hematology.