Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice
Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice
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DOI：
10.1172/jci40572
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发表时间：
2009-12-01
影响因子：
15.9
通讯作者：
Klein, Peter S.
中科院分区：
文献类型：
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作者：
Huang, Jian;Zhang, Yi;Klein, Peter S.
造血干细胞（HSC）的稳态依赖于自我更新和谱系承诺之间的平衡，但调控这一决定的机制尚不清楚。在小鼠中使用功能丧失方法，我们发现糖原合成酶激酶3 （Gsk3）在控制造血干细胞自我更新和分化之间的决定中起着关键作用。BM中Gsk3的破坏以β -连环蛋白依赖的方式短暂地扩大了表型的HSC，这与Writ信号在HSC稳态中的作用一致。然而，在长期造血干细胞功能的分析中，Gsk3的破坏通过激活哺乳动物雷帕霉素靶蛋白（mTOR）逐渐耗尽造血干细胞。mTOR抑制阻止了这种长期的HSC消耗，而β -连环蛋白敲除则加剧了这种消耗。因此，GSK-3调节小鼠HSC中的Writ和mTOR信号通路，这些途径分别促进HSC自我更新和谱系承诺，因此在雷帕霉素存在下抑制Gsk3扩大了体内HSC库。这些发现确定了GSK-3在小鼠HSC稳态中的意想不到的功能，建议使用目前可用的靶向GSK-3和mTOR的药物来扩大体内HSC的治疗方法，并为在处方GSK-3抑制剂锂的个体中观察到的临床普遍的造血作用提供了令人信服的解释。
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 beta-catenin-dependent manner, consistent with a role for Writ 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 beta-catenin knockout. Thus, GSK-3 regulated both Writ 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.