Nature Medicine
- 12, 89 - 98 (2005)
Published online: 11 December 2005; | doi:10.1038/nm1339
Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulationJennifer J Trowbridge1, 2, Anargyros Xenocostas3, 4, Randall T Moon5 & Mickie Bhatia1, 2, 61
Krembil Centre for Stem Cell Biology, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada, N6A 5K8. 2
Department of Microbiology and Immunology, University of Western Ontario, 1151 Richmond Street, London, Ontario, Canada N6A 5B8. 3
Department of Medicine, University of Western Ontario, 1151 Richmond Street, London, Ontario, Canada N6A 5B8. 4
London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, Canada N6A 5W9. 5
Howard Hughes Medical Institute, Department of Pharmacology and Center for Developmental Biology, University of Washington School of Medicine, Seattle, Washington 98195, USA. 6
Present address: McMaster University, Faculty of Health Sciences, 1200 Main Street West, MDCL 5029, Hamilton, Ontario, Canada
Correspondence should be addressed to Mickie Bhatia mbhatia@mcmaster.ca The in vivo regulation of hematopoietic stem cell (HSC) function is poorly understood. Here, we show that hematopoietic repopulation can be augmented by administration of a glycogen synthase kinase-3 (GSK-3) inhibitor to recipient mice transplanted with mouse or human HSCs. GSK-3 inhibitor treatment improved neutrophil and megakaryocyte recovery, recipient survival and resulted in enhanced sustained long-term repopulation. The output of primitive Lin-c-Kit+Sca-1+ cells and progenitors from HSCs increased upon GSK-3 inhibitor treatment without altering secondary repopulating ability, suggesting that the HSC pool is maintained while overall hematopoietic reconstitution is increased. GSK-3 inhibitors were found to modulate gene targets of Wnt, Hedgehog and Notch pathways in cells comprising the primitive hematopoietic compartment without affecting mature cells. Our study establishes GSK-3 as a specific in vivo modulator of HSC activity, and suggests that administration of GSK-3 inhibitors may provide a clinical means to directly enhance the repopulating capacity of transplanted HSCs.
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