Hematopoietic stem cell transplantation (HSCT) efficacy is often limited by inefficient stem cell delivery to the bone marrow and challenges in maintaining transplanted hematopoietic stem cell (HSC) pools. We investigated the impact of modulating α1,3-fucosylation on human peripheral blood CD34+ HSCs, a modification known to improve E-selectin binding through sialyl Lewis X (sLex) expression. Our findings demonstrate that fucosylation-enhanced HSCs exhibit improved rolling by forming elongated tethers and slings, leading to stronger adhesion to E-selectin. This enhanced adhesion facilitated increased homing and engraftment of fucosylated HSCs in the bone marrow and spleen of immunocompromised mice, while inhibiting fucosylation with 2-Fluoro-fucose (2FF) significantly impaired these processes.Further, phosphoproteomic and transcriptomic analyses revealed that enhanced E-selectin binding in fucosylated cells activates key intracellular signaling pathways. Notably, Rho-GTPases, associated with migration and adhesion, and EGFR/PI3K/AKT/mTOR and MAPK pathways, linked to cell cycling, were stimulated. We observed that fucosylation stimulates cell cycling, boosting self-renewal and engraftment, while also enhancing HSC adhesion, quiescence, and marrow retention. These changes appear to preserve long-term stemness, suggesting a multifaceted role for fucosylation in regulating both short-term engraftment and durable hematopoietic reconstitution. This study provides a comprehensive mechanistic understanding of how fucosylation impacts HSC function, highlighting its potential as a powerful strategy to improve HSCT outcomes by optimizing stem cell delivery, engraftment, and long-term hematopoietic reconstitution

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2025
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