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 9

Role of osteoclasts in UDP-Glc–mediated HSPC mobilization.

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Role of osteoclasts in UDP-Glc–mediated HSPC mobilization. (A) op/op mut...
(A) op/op mutant mice (n = 6/group) and littermate controls (n = 10/group) were treated with vehicle or UDP-Glc. HSPC mobilization was assessed by measuring the numbers of LSK and SLAM LSK cells in PB. In the representative images of TRAP staining, arrowheads indicate TRAP-positive cells. Scale bar: 50 μM. (B) P2rx7–/– KO and WT controls (n = 10/group) were treated with vehicle or UDP-Glc. HSPC mobilization was assessed as described in A. In the representative images of TRAP staining, osteoclasts are present at high numbers at 6 weeks of age in P2rx7–/– KO mouse. Data were obtained from 6- to 8-week-old animals. Arrowheads indicate TRAP-positive cells. Scale bar: 50 μM. (C) B6 mice were injected as described for Figure 4A. Bone marrow cells were collected from each treatment group and stained with indicated antibodies. Data represent 3 independent experiments. (D) Bone marrow mononuclear cells were isolated from B6 mice. To determine the protease activity, bone marrow supernatants were analyzed by zymogram analysis as described in the Methods. The intensity of the zymogram bands was analyzed utilizing densitometry, represented as fold change relative to vehicle-treated mice. Similar results were observed in 3 independent experiments. Data are mean ± SD. *P < 0.05, **P < 0.01; #P < 0.05, ##P < 0.01 vs. P2rx7+/+ CTL.