Surface fucosylation of human cord blood cells augments binding to P-selectin and E-selectin and enhances engraftment in bone marrow

Abstract

AbstractMurine hematopoietic stem and progenitor cells (HSPCs) home to bone marrow in part by rolling on P-selectin and E-selectin expressed on endothelial cells. Human adult CD34+ cells, which are enriched in HSPCs, roll on endothelial selectins in bone marrow vessels of nonobese diabetic/severe combined immune deficiency (NOD/SCID) mice. Many human umbilical cord blood (CB) CD34+ cells do not roll in these vessels, in part because of an uncharacterized defect in binding to P-selectin. Selectin ligands must be α1-3 fucosylated to form glycan determinants such as sialyl Lewis x (sLex). We found that inadequate α1-3 fucosylation of CB CD34+ cells, particularly CD34+CD38–/low cells that are highly enriched in HSPCs, caused them to bind poorly to E-selectin as well as to P-selectin. Treatment of CB CD34+ cells with guanosine diphosphate (GDP) fucose and exogenous α1-3 fucosyltransferase VI increased cell-surface sLex determinants, augmented binding to fluid-phase P- and E-selectin, and improved cell rolling on P- and E-selectin under flow. Similar treatment of CB mononuclear cells enhanced engraftment of human hematopoietic cells in bone marrows of irradiated NOD/SCID mice. These observations suggest that α1-3 fucosylation of CB cells might be a simple and effective method to improve hematopoietic cell homing to and engraftment in bone marrows of patients receiving CB transplants.