美国爱因斯坦医学院Keisuke Ito研究团队发现，线粒体NADPH-胆固醇轴调节细胞外囊泡的生物生成以支持造血干细胞的命运。这一研究成果发表在2024年3月7日出版的国际学术期刊《细胞—干细胞》上。

研究人员发现在造血谱系中，造血干细胞（HSC）拥有最大的线粒体NADPH池，这是HSC正常命运和平衡所必需的。HSC转录组的生物信息学分析、生化试验以及脂肪酸氧化（FAO）的基因失活均表明，FAO产生的NADPH可促进HSC中胆固醇的合成。干扰FAO会扰乱线粒体NADPH在单个造血干细胞分裂时向相应子细胞的分离。

重要的是，研究人员发现FAO-NADPH-胆固醇轴驱动着HSC中细胞外囊泡（EV）的生物生成和释放，而抑制EV信号传导会损害HSC的自我更新。

这些数据揭示了线粒体NADPH-胆固醇轴对造血稳态所需的EV生物发生的作用，并强调了HSC命运决定的非随机性。

研究人员表示，线粒体FAO是HSC自我更新的必要条件；然而，线粒体代谢控制HSC命运的机制仍然未知。

附：英文原文

Title: A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate

Author: Massimo Bonora, Claudia Morganti, Nick van Gastel, Kyoko Ito, Enrica Calura, Ilaria Zanolla, Letizia Ferroni, Yang Zhang, Yookyung Jung, Gabriele Sales, Paolo Martini, Takahisa Nakamura, Francesco Massimo Lasorsa, Toren Finkel, Charles P. Lin, Barbara Zavan, Paolo Pinton, Irene Georgakoudi, Chiara Romualdi, David T. Scadden, Keisuke Ito

Issue&Volume: 2024/03/07

Abstract: Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.

DOI: 10.1016/j.stem.2024.02.004

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00047-X