METTL3正调控人胚胎干细胞来源的NK细胞的发育和细胞毒性。

IF 2.9 4区 医学 Q2 CELL BIOLOGY
Cellular immunology Pub Date : 2025-09-01 Epub Date: 2025-08-07 DOI:10.1016/j.cellimm.2025.105011
Xiaofeng Yin, Zhaohui Zhang, Jiaxing Qiu, Yuxing Gong, Qinghua Bi, Meng Meng, Qiangqiang Lai, Hongchen Wang, Shaochang Zhou, Yuan Gao, Lingling Zhang, Wei Wu, Liang Song, Junping Wang, Fangjie Wang, Zhaoyang Zhong, Youcai Deng
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引用次数: 0

摘要

人类胚胎干细胞衍生的NK细胞(hESC-NK)或诱导多能干细胞衍生的NK细胞在癌症治疗的临床试验中已经证明了有效性和安全性,并为研究人类NK细胞发育机制和效应功能提供了有价值的工具。我们之前证明甲基化酶METTL3对小鼠NK细胞的发育和效应功能至关重要,但其在人类NK细胞中的作用尚不清楚。在此,我们使用慢病毒传递的短发夹(sh) RNA构建了METTL3表达降低的H1 ESC菌株,并通过两阶段分化系统生成hESC-NK细胞。我们的研究结果表明,METTL3在hESCs中的敲低降低了胚胎样体(EBs)形成过程中造血干细胞和祖细胞(HSPCs, CD34+细胞)的比例,并损害了随后向成熟NK细胞的分化。此外,shMETTL3-ESC衍生的ESC-NK细胞(称为shMETTL3-ESC- nk)显示出抗肿瘤活性受损,这可以通过下调关键效应物(穿孔素、颗粒酶B和IFN-γ)的mRNA和蛋白水平以及降低对靶细胞的细胞毒性来证明。此外,shMETTL3-ESC-NK细胞中T-BET和EOMES的mRNA和蛋白水平均显著下调。这些转录因子对NK细胞的发育和细胞毒性至关重要,它们的下调可能是shMETTL3-ESC-NK细胞成熟缺陷的基础。总的来说,我们的研究阐明了METTL3促进hESC-NK细胞的发育、成熟和细胞毒性,总结了之前在小鼠NK细胞中的报道。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
METTL3 positively regulates the development and cytotoxicity of human embryonic stem cells-derived NK cells.

Human embryonic stem cell-derived NK (hESC-NK) cells or induced pluripotent stem cell derived NK cells have demonstrated efficacy and safety in clinical trials for cancer therapy and serve as a valuable tool for studying the mechanisms of human NK cell development and effector functions. We previously demonstrated that the methylase METTL3 was essential for the development and effector functions of murine NK cells, but its role in human NK cells remained unknown. Herein, we constructed an H1 ESC strain with reduced METTL3 expression using lentivirus-delivered short hairpin (sh) RNA and generated hESC-NK cells via a two-stage differentiation system. Our findings demonstrated that METTL3 knockdown in hESCs reduced the proportion of hematopoietic stem and progenitor cells (HSPCs, CD34+ cells) during embryoid bodies (EBs) formation, and impaired subsequent differentiation into mature NK cells. Moreover, ESC-NK cells derived from shMETTL3-ESC (called shMETTL3-ESC-NK) showed impaired anti-tumor activity, evidenced by downregulation of mRNA and protein levels of critical effectors (perforin, granzyme B and IFN-γ) and reduced cytotoxicity against target cells. Furthermore, both mRNA and protein levels of T-BET and EOMES were significantly down-regulated in shMETTL3-ESC-NK cells. These transcription factors are critical for NK cell development and cytotoxicity, and their downregulation may underlie the maturation defects of shMETTL3-ESC-NK cells. Collectively, our study elucidates that METTL3 promotes the development, maturation and cytotoxicity of hESC-NK cells, recapitulating previous reports in murine NK cells.

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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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