Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation.
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.
Trowbridge
Jennifer J
JJ
Krembil Centre for Stem Cell Biology, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada, N6A 5K8.
Xenocostas
Anargyros
A
Moon
Randall T
RT
Bhatia
Mickie
M
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
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