RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment
RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment
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DOI：
10.1038/s41375-023-02097-3
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发表时间：
2023-11-30
期刊：
影响因子：
11.4
通讯作者：
Liu，Lingbo
中科院分区：
文献类型：
--
作者：
Chen，Ying;Wen，Jin;Liu，Lingbo
白血病干细胞（LSC）的命运是由其固有的机制和串扰与他们的小生境。虽然LSC被证实通过重新开始衰老而被根除，但LSC抵抗衰老和重塑生态位以获得适合干性的微环境的特定关键调节因子仍然未知。在这里，我们发现调节外泌体分泌的基因RAB 27 B在LSC中过表达，并与急性髓性白血病（AML）患者的不良预后相关。在体外和体内，LSC中增加的RAB 27 B阻止了它们的衰老并保持了它们的干性。在机械上，LSC中增加的RAB 27 B表达通过直接组合选择性地促进富含衰老诱导蛋白的外泌体的装载和释放。此外，RAB27 B调节的LSC衍生的外泌体重塑了间充质干细胞（MSC）的生态位并诱导衰老，其中RAB27 B表达增加。相反，衰老MSC中增加的RAB 27 B通过选择性分泌富含干性促进蛋白的外泌体而促进离体和体内LSC维持。因此，我们鉴定了在LSC和它们的受教育的衰老MSC中特异性增加的RAB 27 B作为LSC抵抗衰老和通过经由选择性外泌体排泄与其小生境的串扰维持的中枢分子。
The fate of leukaemia stem cells (LSCs) is determined by both their inherent mechanisms and crosstalk with their niches. Although LSCs were confirmed to be eradicated by restarting senescence, the specific key regulators of LSC resistance to senescence and remodelling of the niche to obtain a microenvironment suitable for stemness remain unknown. Here, we found that RAB27B, a gene regulating exosome secretion, was overexpressed in LSCs and associated with the poor prognosis of acute myeloid leukaemia (AML) patients. The increased RAB27B in LSCs prevented their senescence and maintained their stemness in vitro and in vivo. Mechanically, the increased RAB27B expression in LSCs selectively promoted the loading and release of exosomes rich in senescence-inducing proteins by direct combination. Furthermore, RAB27B-regulated LSC-derived exosomes remodelled the niche and induced senescence of mesenchymal stem cells (MSCs) with increased RAB27B expression ex vivo and in vivo. The increased RAB27B in the senescent MSCs conversely promoted LSC maintenance ex vivo and in vivo via selective excretion of exosomes rich in stemness-promoting proteins. Therefore, we identified the specifically increased RAB27B in LSCs and their educated senescent MSCs as a hub molecule for LSC resistance to senescence and maintenance through crosstalk with its niche via selective exosome excretion.