The nucleotide sugar UDP-glucose mobilizes long-term repopulating primitive hematopoietic cells

Abstract

Hematopoietic stem progenitor cells (HSPCs) are present in very small numbers in the circulating blood in steady-state conditions. In response to stress or injury, HSPCs are primed to migrate out of their niche to peripheral blood. Mobilized HSPCs are now commonly used as stem cell sources due to faster engraftment and reduced risk of posttransplant infection. In this study, we demonstrated that a nucleotide sugar, UDP-glucose, which is released into extracellular fluids in response to stress, mediates HSPC mobilization. UDP-glucosemobilized cells possessed the capacity to achieve long-term repopulation in lethally irradiated animals and the ability to differentiate into multi-lineage blood cells. Compared with G-CSF-mobilized cells, UDP-glucose-mobilized cells preferentially supported long-term repopulation and exhibited lymphoid-biased differentiation, suggesting that UDP-glucose triggers the mobilization of functionally distinct subsets of HSPCs. Furthermore, co-administration of UDP-glucose and G-CSF led to greater HSPC mobilization than G-CSF alone. Administration of the antioxidant agent NAC significantly reduced UDP-glucose-induced mobilization, coinciding with a reduction in RANKL and osteoclastogenesis. These findings provide direct evidence demonstrating a potential role for UDP-glucose in HSPC mobilization and may provide an attractive strategy to improve the yield of stem cells in poor-mobilizing allogeneic or autologous donors.

Plasma Elevation of Vascular Endothelial Growth Factor Leads to the Reduction of Mouse Hematopoietic and Mesenchymal Stem/Progenitor Cells in the Bone Marrow

“…Notably, a recent study showed that HSPCs could be mobilized from the BM into the circulation by administration of a prostagrandin E 2 (PGE 2 ) inhibitor, and this effect was independent of CXCL12-CXCR4 signaling [32]. A nucleotide sugar, uridine diphosphate (UDP)-glucose, has also been shown to mobilize subsets of HSPCs functionally distinct from those mobilized by G-CSF, suggesting that UDP-glucose-induced HSPC mobilization would be mediated, at least in part, by different mechanisms from G-CSF [33]. Thus, it would be of interest to examine whether VEGF could influence the levels of BM PGE 2 and/or plasma UDP glucose.…”

Current Developments in Mobilization of Hematopoietic Stem and Progenitor Cells and Their Interaction with Niches in Bone Marrow

“…UDP-glc has been shown to mobilize long-term repopulating HSPCs, and co-administration of UDP-glc and G-CSF led to greater HSPC mobilization than G-CSF alone [143]. In competitive repopulation experiments, HSPCs mobilized with UDP-glc plus G-CSF repopulated better than HSPCs mobilized with G-CSF alone.…”

“…In competitive repopulation experiments, HSPCs mobilized with UDP-glc plus G-CSF repopulated better than HSPCs mobilized with G-CSF alone. In comparison with G-CSF, UDPglc-mobilized HSPCs exhibited a more lymphoid-biased differentiation capacity, indicating that UDP-glc mobilizes a functionally distinct subset of HSPCs [143]. In contrast, inhibition experiments showed that reactive oxygen species (ROS) are mediators of UDPglc-mediated HSPC mobilization.…”

“…Application of the ROS inhibitor N-acetyl-L-cysteine (NAC) was able to significantly abrogate UDPglc-induced HSPC mobilization. Kook et al suggest that ROS induce enhancement in receptor activator of nuclear factor kappa-B ligand (RANKL) expression and a RANKL-induced osteoclast differentiation, leading to HSPC mobilization [143].…”

New agents in HSC mobilization

“…The natural nucleotide sugar uridine diphosphate glucose (UDP-Glc), normally involved in metabolism and a precursor to glycogen synthesis, was recently shown to selectively mobilize HSC when used alone or in combination with G-CSF [95]. Of note, sorted PB HSC from UDP-Glc-mobilized mice possessed superior long-term engraftment potential compared to phenotypically equivalent HSC harvested from G-CSF-mobilized blood, which is consistent with previous reports indicating G-CSFmobilized HSC have reduced capacity to sustain longterm hematopoiesis [87,96].…”