The nucleotide sugar UDP-glucose mobilizes long-term repopulating primitive hematopoietic cells
Sungho Kook, … , Sean Bong Lee, Byeong-Chel Lee
Sungho Kook, … , Sean Bong Lee, Byeong-Chel Lee
Published July 25, 2013
Citation Information: J Clin Invest. 2013;123(8):3420-3435. https://doi.org/10.1172/JCI64060.
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Research Article Hematology

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-glucose–mobilized 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.

Authors

Sungho Kook, Joonseok Cho, Sean Bong Lee, Byeong-Chel Lee

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Figure 10

Analysis of HSPC migration in response to UDP and UDP-Glc.

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Analysis of HSPC migration in response to UDP and UDP-Glc. (A) Mice were...
(A) Mice were treated as described in Figure 8. Expression levels of CXCR4 were determined in bone marrow and PB cells after gating on LSK or SLAM LSK subsets. Data are from at least 2 independent experiments with 4 mice/group. (B and C) B6 mice (n = 7/group) were treated with UDP-Glc or UDP-Glc/NAC as described in A. PB cells (CD45.2) were collected and injected into recipient mice (CD45.1.2) (6 × 106/mouse), which were conditioned 24 hours before injection. Animals were sacrificed 12–14 hours after injection. (B) Recipient bone marrow cells were analyzed for expression of donor cell marker (CD45.2). (C) CD45.2+ cells were gated and analyzed for the presence of LSK cells. (D) B6 mice (n = 5/group) were injected with UDP (200 mg/kg), UDP-Glc (200 mg/kg), or UDP plus UDP-Glc and PB LSK cells quantified. (E) Chemotaxis assays were performed as described in Figure 1E. Lin– bone marrow cells were placed in the upper well (106/well); UDP, UDP-Glc, or UDP plus UDP-Glc (10 μM each) was placed in the lower wells. Cells that migrated to lower wells were collected and stained for Sca-1 and c-Kit. Data represent 2 independent experiments, each with duplicate wells per treatment condition. Data are mean ± SD. *P < 0.05, **P < 0.01.