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Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2020-02-26 , DOI: 10.1016/j.stem.2020.01.013 Raymond Liang 1 , Tasleem Arif 2 , Svetlana Kalmykova 3 , Artem Kasianov 4 , Miao Lin 2 , Vijay Menon 2 , Jiajing Qiu 2 , Jeffrey M Bernitz 2 , Kateri Moore 2 , Fangming Lin 5 , Deanna L Benson 6 , Nikolaos Tzavaras 6 , Milind Mahajan 7 , Dmitri Papatsenko 3 , Saghi Ghaffari 8
Cell Stem Cell ( IF 19.8 ) Pub Date : 2020-02-26 , DOI: 10.1016/j.stem.2020.01.013 Raymond Liang 1 , Tasleem Arif 2 , Svetlana Kalmykova 3 , Artem Kasianov 4 , Miao Lin 2 , Vijay Menon 2 , Jiajing Qiu 2 , Jeffrey M Bernitz 2 , Kateri Moore 2 , Fangming Lin 5 , Deanna L Benson 6 , Nikolaos Tzavaras 6 , Milind Mahajan 7 , Dmitri Papatsenko 3 , Saghi Ghaffari 8
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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.
中文翻译：
抑制溶酶体活性可保持造血干细胞的静止和效力。
静态是一项基本属性，可在整个生命过程中维持造血干细胞（HSC）的效力。人们认为静止的HSC依靠糖酵解获得能量，但是HSC的整体代谢特性仍然难以捉摸。使用包括单细胞RNA测序（RNA-seq）在内的组合方法，我们表明线粒体膜电位（MMP）可以区分静止的与循环启动的HSC。我们发现引发的而不是静止的HSC容易依赖糖酵解。值得注意的是，体内对糖酵解的抑制作用增强了初免HSC的竞争性再繁殖能力。我们进一步表明，HSC静止性由大量的大溶酶体维持。HSC中溶酶体激活的抑制导致溶酶体的进一步扩大，同时抑制了葡萄糖的摄取。这也诱导线粒体的溶酶体隔离增加，并在体内使引发的HSC的竞争性再繁殖能力提高了90倍以上。这些发现表明，抑制溶酶体活性可以保持HSC的静止和效力，并且可能与治疗有关。
更新日期：2020-02-28
中文翻译：
抑制溶酶体活性可保持造血干细胞的静止和效力。
静态是一项基本属性，可在整个生命过程中维持造血干细胞（HSC）的效力。人们认为静止的HSC依靠糖酵解获得能量，但是HSC的整体代谢特性仍然难以捉摸。使用包括单细胞RNA测序（RNA-seq）在内的组合方法，我们表明线粒体膜电位（MMP）可以区分静止的与循环启动的HSC。我们发现引发的而不是静止的HSC容易依赖糖酵解。值得注意的是，体内对糖酵解的抑制作用增强了初免HSC的竞争性再繁殖能力。我们进一步表明，HSC静止性由大量的大溶酶体维持。HSC中溶酶体激活的抑制导致溶酶体的进一步扩大，同时抑制了葡萄糖的摄取。这也诱导线粒体的溶酶体隔离增加，并在体内使引发的HSC的竞争性再繁殖能力提高了90倍以上。这些发现表明，抑制溶酶体活性可以保持HSC的静止和效力，并且可能与治疗有关。
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