Department of Cell, Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Developmental and Stem Cell Biology Multidisciplinary Training Area, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Department of Cell, Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Cell Stem Cell. 2020 Mar 5;26(3):359-376.e7. doi: 10.1016/j.stem.2020.01.013. Epub 2020 Feb 27.
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.
静止是维持造血干细胞（HSC）活力的基本特性。静止的 HSC 被认为依赖糖酵解来提供能量，但 HSC 的整体代谢特性仍然难以捉摸。我们使用包括单细胞 RNA 测序（RNA-seq）在内的联合方法表明，线粒体膜电位（MMP）可区分静止和周期激活的 HSC。我们发现，激活但非静止的 HSC 很容易依赖糖酵解。值得注意的是，体内抑制糖酵解可增强激活 HSC 的竞争重编程能力。我们进一步表明，HSC 的静止是通过大量溶酶体维持的。在 HSC 中抑制溶酶体的激活会导致溶酶体进一步增大，同时抑制葡萄糖摄取。这也诱导了溶酶体对线粒体的摄取增加，并在体内将激活的 HSC 的竞争重编程能力提高了 90 多倍。这些发现表明，抑制溶酶体活性可维持 HSC 的静止和活力，这可能具有治疗相关性。
