Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency.
Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency.
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DOI：
10.1016/j.stem.2020.01.013
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发表时间：
2020-03-05
期刊：
影响因子：
23.9
通讯作者：
Ghaffari S
中科院分区：
文献类型：
--
作者：
Liang R;Arif T;Kalmykova S;Kasianov A;Lin M;Menon V;Qiu J;Bernitz JM;Moore K;Lin F;Benson DL;Tzavaras N;Mahajan M;Papatsenko D;Ghaffari S
静止是维持造血干细胞（HSC）在整个生命周期中的潜能的基本特性。静止的HSC被认为依赖于糖酵解获得能量，但HSC的整体代谢特性仍然难以捉摸。使用组合方法，包括单细胞RNA测序（RNA-seq），我们表明线粒体膜电位（MMP）区分静止和周期启动的HSC。我们发现，启动，但不是静止，HSC很容易依赖于糖酵解。值得注意的是，体内抑制糖酵解增强了引发的HSC的竞争性再增殖能力。我们进一步表明，HSC的静止是由大量的大溶酶体维持的。抑制HSC中的溶酶体活化导致溶酶体进一步增大，同时抑制葡萄糖摄取。这也诱导线粒体的溶酶体隔离增加，并在体内将引发的HSC的竞争性再增殖能力增强90倍以上。这些发现表明，抑制溶酶体活性保留HSC静止和效力，并且可能具有治疗相关性。造血干细胞（HSC）的静止和潜能被认为是通过糖酵解来维持的。通过利用线粒体的异质性，Liang，Arif等人发现，活化的而不是静止的HSC使用糖酵解来获得能量。大量的溶酶体维持静止状态，溶酶体的抑制使HSC的效力提高90倍以上。
Quiescence is a fundamental property that maintains hematopoietic stem cell (HSC) potency throughout life. Quiescent HSCs are thought to rely on glycolysis for their energy, but the overall metabolic properties of HSCs remain elusive. Using combined approaches, including single-cell RNA sequencing (RNA-seq), we show that mitochondrial membrane potential (MMP) distinguishes quiescent from cycling-primed HSCs. We found that primed, but not quiescent, HSCs relied readily on glycolysis. Notably, in vivo inhibition of glycolysis enhanced the competitive repopulation ability of primed HSCs. We further show that HSC quiescence is maintained by an abundance of large lysosomes. Repression of lysosomal activation in HSCs led to further enlargement of lysosomes while suppressing glucose uptake. This also induced increased lysosomal sequestration of mitochondria and enhanced the competitive repopulation ability of primed HSCs by over 90-fold in vivo. These findings show that restraining lysosomal activity preserves HSC quiescence and potency and may be therapeutically relevant. The quiescence and potency of hematopoietic stem cells (HSCs) are thought to be maintained by glycolysis. By exploiting mitochondrial heterogeneity, Liang, Arif, et al. uncover that activated, but not quiescent, HSCs use glycolysis for energy. Quiescence is maintained by an abundance of lysosomes whose repression enhances HSC potency by over 90-fold.
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DOI：
10.1084/jem.20161087
发表时间：
2017-03-06
期刊：
The Journal of experimental medicine
影响因子：
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影响因子：
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发表时间：
2008-09-29
期刊：
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影响因子：
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作者：
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