Fucose‐deficient hematopoietic stem cells have decreased self‐renewal and aberrant marrow niche occupancy

BACKGROUND: Modification of Notch receptors by O‐linked fucose and its further elongation by the Fringe family of glycosyltransferase has been shown to be important for Notch signaling activation. Our recent studies disclose a myeloproliferative phenotype, hematopoietic stem cell (HSC) dysfunction, and abnormal Notch signaling in mice deficient in FX, which is required for fucosylation of a number of proteins including Notch. The purpose of this study was to assess the self‐renewal and stem cell niche features of fucose‐deficient HSCs. STUDY DESIGN AND METHODS: Homeostasis and maintenance of HSCs derived from FX^?/? mice were studied by serial bone marrow transplantation, homing assay, and cell cycle analysis. Two‐photon intravital microscopy was performed to visualize and compare the in vivo marrow niche occupancy by fucose‐deficient and wild‐type (WT) HSCs. RESULTS: Marrow progenitors from FX^?/? mice had mild homing defects that could be partially prevented by exogenous fucose supplementation. Fucose‐deficient HSCs from FX^?/? mice displayed decreased self‐renewal capability compared with the WT controls. This is accompanied with their increased cell cycling activity and suppressed Notch ligand binding. When tracked in vivo by two‐photon intravital imaging, the fucose‐deficient HSCs were found localized farther from the endosteum of the calvarium marrow than the WT HSCs. CONCLUSIONS: The current reported aberrant niche occupancy by HSCs from FX^?/? mice, in the context of a faulty blood lineage homeostasis and HSC dysfunction in mice expressing Notch receptors deficient in O‐fucosylation, suggests that fucosylation‐modified Notch receptor may represent a novel extrinsic regulator for HSC engraftment and HSC niche maintenance.