Chemokines Stimulate Bidirectional Migration of Human Mesenchymal Stem Cells Across Bone Marrow Endothelial Cells

Mesenchymal stem cells (MSCs) can be mobilized from the bone marrow and enter the circulation. Conversely, MSCs can be recruited from the circulation and into the bone marrow. For these migratory pathways, MSCs have to traverse the bone marrow endothelium, in a basal-to-apical and apical-to-basal direction, respectively. Here we describe the migratory cues that drive MSC transendothelial migration in both directions with focus on chemokines. Live cell imaging and electron microscopy were used to examine the interaction of human MSCs with human bone marrow endothelial cells (HBMECs), and MSC transmigration analyzed. Chemokines CXCL12, CXCL13, CXCL16, CCL11, and CCL22 significantly enhanced transendothelial migration in an apical-to-basal and basal-to-apical direction, showing preferences in terms of their capacity to stimulate the direction of migration. For apical-to-basal migration CXCL16 was the most effective (6-fold stimulation), with the rank order being CXCL16 > CCL11 > CXCL13 > CCL22 > CXCL12. In the basal-to-apical direction CCL22 was the most effective (5-fold enhancement), with the remaining chemokines being roughly equal. When MSCs interacted with HBMECs they flattened, extended long microvilli (filopodia) and podosome-like protrusions that inserted into the endothelial cells. In conclusion, chemokines enhance the migration of MSCs bidirectionally across HBMECs, with directional preferences shown for different chemokines.