Pivotal role for glycogen synthase kinase–3 in hematopoietic stem cell homeostasis in mice
Jian Huang, … , Stephen G. Emerson, Peter S. Klein
Jian Huang, … , Stephen G. Emerson, Peter S. Klein
Published November 23, 2009
Citation Information: J Clin Invest. 2009;119(12):3519-3529. https://doi.org/10.1172/JCI40572.
View: Text | PDF
Research Article Hematology

Pivotal role for glycogen synthase kinase–3 in hematopoietic stem cell homeostasis in mice

Abstract

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 β-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 β-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.

Authors

Jian Huang, Yi Zhang, Alexey Bersenev, W. Timothy O’Brien, Wei Tong, Stephen G. Emerson, Peter S. Klein

×

Figure 8

GSK-3 functions in 2 major pathways to regulate HSC self renewal and lineage commitment.

Options: View larger image (or click on image) Download as PowerPoint
GSK-3 functions in 2 major pathways to regulate HSC self renewal and lin...
Inhibition of GSK-3 activates Wnt and mTOR signaling. In the canonical Wnt pathway, GSK-3 and β-catenin bind to the Axin complex, along with APC. GSK-3 phosphorylates β-catenin, targeting it for rapid destruction. Wnt binding to the Fz/Lrp receptor complex causes inhibition of GSK-3, which in turn stabilizes β-catenin and activates Wnt target genes that promote progenitor proliferation and self renewal. In PI3K/PTEN-regulated pathways, growth factors (GFs) bind to surface receptors and activate PI3K, leading to activation of Akt, whereas PTEN inhibits activation of Akt. Once activated, Akt phosphorylates and inhibits GSK-3. GSK-3 phosphorylates Tsc2, inhibiting the mTOR pathway. Thus, inhibition of GSK-3 activates mTOR and promotes proliferation and exit from the LT-HSC pool. Inhibition of GSK-3 thus activates distinct downstream signaling pathways that have opposing functions in HSC renewal and differentiation.