Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice
- PMID: 19959876
- PMCID: PMC2786808
- DOI: 10.1172/JCI40572
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 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.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2786808/bin/JCI40572.f1.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2786808/bin/JCI40572.f2.gif)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2786808/bin/JCI40572.f3.gif)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2786808/bin/JCI40572.f4.gif)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2786808/bin/JCI40572.f5.gif)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2786808/bin/JCI40572.f6.gif)
![Figure 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2786808/bin/JCI40572.f7.gif)
![Figure 8](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2786808/bin/JCI40572.f8.gif)
Similar articles
-
Rapamycin enhances long-term hematopoietic reconstitution of ex vivo expanded mouse hematopoietic stem cells by inhibiting senescence.Transplantation. 2014 Jan 15;97(1):20-9. doi: 10.1097/TP.0b013e3182a7fcf8. Transplantation. 2014. PMID: 24092377 Free PMC article.
-
Cooperation between both Wnt/{beta}-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion.Genes Dev. 2011 Sep 15;25(18):1928-42. doi: 10.1101/gad.17421911. Epub 2011 Sep 2. Genes Dev. 2011. PMID: 21890648 Free PMC article.
-
Glycogen synthase kinase-3beta inhibition preserves hematopoietic stem cell activity and inhibits leukemic cell growth.Stem Cells. 2008 May;26(5):1288-97. doi: 10.1634/stemcells.2007-0600. Epub 2008 Mar 6. Stem Cells. 2008. PMID: 18323411
-
The Akt-mTOR network at the interface of hematopoietic stem cell homeostasis.Exp Hematol. 2021 Nov;103:15-23. doi: 10.1016/j.exphem.2021.08.009. Epub 2021 Aug 28. Exp Hematol. 2021. PMID: 34464661 Review.
-
Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention.Leukemia. 2014 Jan;28(1):15-33. doi: 10.1038/leu.2013.184. Epub 2013 Jun 19. Leukemia. 2014. PMID: 23778311 Free PMC article. Review.
Cited by
-
A novel study on CXXC5: unraveling its regulatory mechanisms in hematopoietic stem cell biology through proteomics and gene editing.Genes Genomics. 2024 Aug 16. doi: 10.1007/s13258-024-01540-8. Online ahead of print. Genes Genomics. 2024. PMID: 39150611
-
Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Alveolar Epithelial Cell Proliferation and Lung Regeneration in the Lipopolysaccharide-Induced Acute Lung Injury Mouse Model.Int J Mol Sci. 2024 Jan 20;25(2):1279. doi: 10.3390/ijms25021279. Int J Mol Sci. 2024. PMID: 38279281 Free PMC article.
-
Rare A360T Mutation Alters GSK3β(Ser9) Binding in the Cytosolic Loop of Presenilin 1, Influencing β-Catenin Nuclear Localization and Pro-Death Gene Expression in Alzheimer's Disease Case.Int J Mol Sci. 2023 Nov 30;24(23):16999. doi: 10.3390/ijms242316999. Int J Mol Sci. 2023. PMID: 38069323 Free PMC article.
-
Loss of GSK3β in hematopoietic stem cells results in normal hematopoiesis in mice.Blood Adv. 2023 Dec 12;7(23):7185-7189. doi: 10.1182/bloodadvances.2022008094. Blood Adv. 2023. PMID: 37922427 Free PMC article. No abstract available.
-
When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex.Cells. 2023 Sep 12;12(18):2256. doi: 10.3390/cells12182256. Cells. 2023. PMID: 37759479 Free PMC article. Review.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Miscellaneous