美国西奈山伊坎医学院Saghi Ghaffari课题组的最新研究发现抑制溶酶体活性可保持造血干细胞（HSC）的静止性和效力。2020年2月27日出版的《细胞-干细胞》在线发表了这项成果。

使用包括单细胞RNA测序（RNA-seq）在内的组合方法，研究人员发现线粒体膜电位（MMP）可以从循环驯化的HSC中区分出静止的HSC。研究发现驯化而非静止的HSC容易依赖糖酵解。值得注意的是，在体内抑制糖酵解增强了驯化HSC的竞争性再繁殖能力。进一步实验表明，大量溶酶体可以维持HSC的静止状态。抑制.HSC中溶酶体的活化导致溶酶体进一步扩大，同时抑制了葡萄糖的摄取。这诱导线粒体溶酶体螯合增加，并在体内使驯化HSC的竞争性再繁殖能力提高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，并且可能与治疗相关。

据了解，静止是维持生命中造血干细胞（HSC）效能的一项基本属性。人们认为静止HSC的能量来源依赖于糖酵解，但HSC的整体代谢特性仍然未知。

附：英文原文

Title: Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency

Author: Raymond Liang, Tasleem Arif, Svetlana Kalmykova, Artem Kasianov, Miao Lin, Vijay Menon, Jiajing Qiu, Jeffrey M. Bernitz, Kateri Moore, Fangming Lin, Deanna L. Benson, Nikolaos Tzavaras, Milind Mahajan, Dmitri Papatsenko, Saghi Ghaffari

Issue&Volume: 2020-02-27

Abstract: Quiescence is a fundamental property that maintains hematopoietic stem cell (HSC)potency throughout life. Quiescent HSCs are thought to rely on glycolysis for theirenergy, but the overall metabolic properties of HSCs remain elusive. Using combinedapproaches, including single-cell RNA sequencing (RNA-seq), we show that mitochondrialmembrane potential (MMP) distinguishes quiescent from cycling-primed HSCs. We foundthat primed, but not quiescent, HSCs relied readily on glycolysis. Notably, in vivo inhibition of glycolysis enhanced the competitive repopulation ability of primedHSCs. 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 lysosomeswhile suppressing glucose uptake. This also induced increased lysosomal sequestrationof mitochondria and enhanced the competitive repopulation ability of primed HSCs byover 90-fold in vivo. These findings show that restraining lysosomal activity preserves HSC quiescenceand potency and may be therapeutically relevant.

DOI: 10.1016/j.stem.2020.01.013

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30013-8