title: Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation.
abstract: 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.
authors.affiliation: Krembil Centre for Stem Cell Biology, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada, N6A 5K8.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Trowbridge
authors.forename: Anargyros
authors.initials: A
authors.lastname: Xenocostas
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Mickie
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D017690:Cell Transplantation; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D053823:Hedgehog Proteins; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology; D051880:Receptors, Notch / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; D051880:Receptors, Notch; D015534:Trans-Activators; D051153:Wnt Proteins; D049452:Green Fluorescent Proteins; D038362:Glycogen Synthase Kinase 3