加拿大大学健康网络John E. Dick和Stephanie Z. Xie等研究人员，合作揭示了鞘脂调节激活蛋白稳态程序来控制人类造血干细胞（HSC）的自我更新。2019年10月17日，《细胞—干细胞》杂志在线发表了这项成果。

研究人员发现跨越人类造血系统鞘脂组的独特联系，并发现鞘脂酶DEGS1的遗传或药理调控改变谱系分化。N-（4-羟苯基）视黄酰胺从静止过渡到细胞活化过程中，对造血干细胞和祖细胞中DEGS1的抑制作用激活了协调的应激途径，该途径在内质网应激和自噬程序上结合，以维持免疫表型和功能性HSC。因此，这项工作确定了鞘脂代谢、蛋白稳态质量控制系统和HSC自我更新之间的联系，并为改善基于HSC的细胞疗法提供了治疗靶点。

据了解，细胞应激反应是平衡维持生命或淘汰HSC进行终生造血的关键决策点。尽管强大的应激源会剔除HSC，但仍不清楚应激程序与维持人类HSC的自我更新特性之间的联系，尤其是在静止退出时，HSC也必须动态改变代谢状态。

附：英文原文

Title: Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal

Author: Stephanie Z. Xie, Laura Garcia-Prat, Veronique Voisin, Robin Ferrari, Olga I. Gan, Elvin Wagenblast, Kerstin B. Kaufmann, Andy G.X. Zeng, Shin-ichiro Takayanagi, Ishita Patel, Esther K. Lee, Joseph Jargstorf, Gareth Holmes, Guy Romm, Kristele Pan, Michelle Shoong, Aditi Vedi, Chiara Luberto, Mark D. Minden, Gary D. Bader, Elisa Laurenti, John E. Dick

Issue&Volume: 17 October 2019

Abstract: 

Cellular stress responses serve as crucial decision points balancing persistence or culling of hematopoietic stem cells (HSCs) for lifelong blood production. Although strong stressors cull HSCs, the linkage between stress programs and self-renewal properties that underlie human HSC maintenance remains unknown, particularly at quiescence exit when HSCs must also dynamically shift metabolic state. Here, we demonstrate distinct wiring of the sphingolipidome across the human hematopoietic hierarchy and find that genetic or pharmacologic modulation of the sphingolipid enzyme DEGS1 regulates lineage differentiation. Inhibition of DEGS1 in hematopoietic stem and progenitor cells during the transition from quiescence to cellular activation with N-(4-hydroxyphenyl) retinamide activates coordinated stress pathways that coalesce on endoplasmic reticulum stress and autophagy programs to maintain immunophenotypic and functional HSCs. Thus, our work identifies a linkage between sphingolipid metabolism, proteostatic quality control systems, and HSC self-renewal and provides therapeutic targets for improving HSC-based cellular therapeutics.

DOI: 10.1016/j.stem.2019.09.008

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30393-5