Pivotal role for glycogen synthase kinase–3 in hematopoietic stem cell homeostasis in mice
Jian Huang, Yi Zhang, Alexey Bersenev, W. Timothy O’Brien, Wei Tong, Stephen G. Emerson, Peter S. Klein
Jian Huang, Yi Zhang, Alexey Bersenev, W. Timothy O’Brien, Wei Tong, Stephen G. Emerson, Peter S. Klein
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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

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Figure 5

β-catenin is required for the increase in HSCs/HPCs induced by Gsk3-rnai.

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β-catenin is required for the increase in HSCs/HPCs induced by Gsk3-rnai...
(A) BM cells were harvested from Mx-Cre;β-cateninfl/fl mice with or without injection of polyI:polyC for 14 days, transduced with control or Gsk3-rnai carrying lentivirus, and transplanted into lethally irradiated recipient mice. After 4 months, percentage and absolute number of HSC-containing LSK fraction were compared among the 4 groups. (B) BM cells were harvested at 4 months from primary recipients of WT and Mx-Cre;β-cateninfl/fl mice transduced with vector control or Gsk3-rnai lentivirus (from primary recipient mice in A) and transplanted into lethally irradiated secondary hosts. After 4 months, percentage and absolute number of HSC-containing LSK fraction were compared among the 4 groups. (C) Summary of serial transplantation data in WT versus β-catenin CKO mice. Shown is fold change in GFP+ LSK cells in recipients of Gsk3-depleted BM normalized to vector control, for otherwise WT primary, secondary, and tertiary recipients as well as for primary and secondary β-catenin CKO recipients. Survival in tertiary recipients of Gsk3/β-catenin–deficient BM was too low for statistical significance. *P < 0.05.