Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice.
Hematopoietic stem cell (HSC) homeostasis depends on the balance between self renewal and lineage commitment, but what regulates this decision is not well understood. Using loss-of-function approaches in mice, we found that glycogen synthase kinase-3 (Gsk3) plays a pivotal role in controlling the decision between self renewal and differentiation of HSCs. Disruption of Gsk3 in BM transiently expanded phenotypic HSCs in a betta-catenin-dependent manner, consistent with a role for Wnt signaling in HSC homeostasis. However, in assays of long-term HSC function, disruption of Gsk3 progressively depleted HSCs through activation of mammalian target of rapamycin (mTOR). This long-term HSC depletion was prevented by mTOR inhibition and exacerbated by betta-catenin knockout. Thus, GSK-3 regulated both Wnt and mTOR signaling in mouse HSCs, with these pathways promoting HSC self renewal and lineage commitment, respectively, such that inhibition of Gsk3 in the presence of rapamycin expanded the HSC pool in vivo. These findings identify unexpected functions for GSK-3 in mouse HSC homeostasis, suggest a therapeutic approach to expand HSCs in vivo using currently available medications that target GSK-3 and mTOR, and provide a compelling explanation for the clinically prevalent hematopoietic effects observed in individuals prescribed the GSK-3 inhibitor lithium.
Huang
Jian
J
Department of Medicine (Hematology-Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Zhang
Yi
Y
Bersenev
Alexey
A
O'Brien
W Timothy
WT
Tong
Wei
W
Emerson
Stephen G
SG
Klein
Peter S
PS
D000818:Animals; D016026:Bone Marrow Transplantation; D002352:Carrier Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D051153:Wnt Proteins; D051176:beta Catenin; D008094:Lithium; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3