Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Chengdu, China; Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China; Non-coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, China.
Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Chengdu, China.
Redox Biol. 2022 Aug;54:102392. doi: 10.1016/j.redox.2022.102392. Epub 2022 Jul 2.
Granulocyte-monocyte progenitors (GMPs) differentiate into both neutrophils and monocytes. Recently, uni-potential neutrophil progenitors have been identified both in mice and humans using an array of surface markers. However, how human GMPs commit to neutrophil progenitors and the regulatory mechanisms of fate determination remain incompletely understood. In the present study, we established a human neutrophil deficiency model using the small molecule alpha-lipoic acid. Using this neutrophil deficiency model, we determined that the neutrophil progenitor commitment process from CD371 CD115 GMPs defined by CD34 and CD15 and discovered that critical signals generated by RNA splicing and rRNA biogenesis regulate the process of early commitment for human early neutrophil progenitors derived from CD371 CD115 GMPs. These processes were elucidated by single-cell RNA sequencing both in vitro and in vivo derived cells. Sequentially, we identified that the transcription factor ELK1 is essential for human neutrophil lineage commitment using the alpha-lipoic acid (ALA)-inducing neutrophil deficiency model. Finally, we also revealed differential roles for long-ELK1 and short-ELK1, balanced by SF3B1, in the commitment process of neutrophil progenitors. Taken together, we discovered a novel function of ALA in regulating neutrophil lineage specification and identified that the SF3B1-ELK axis regulates the commitment of human neutrophil progenitors from CD371 CD115 GMPs.
粒细胞-单核细胞祖细胞 (GMP) 可分化为中性粒细胞和单核细胞。最近，使用一系列表面标志物在小鼠和人类中均鉴定出了单潜能中性粒细胞祖细胞。然而，人类 GMP 如何向中性粒细胞祖细胞分化以及命运决定的调节机制仍不完全清楚。在本研究中，我们使用小分子α-硫辛酸建立了人类中性粒细胞缺乏模型。使用该中性粒细胞缺乏模型，我们确定了 CD34 和 CD15 定义的 CD371 CD115 GMP 向中性粒细胞祖细胞的分化过程，并发现由 RNA 剪接和 rRNA 生物发生产生的关键信号调节了源自 CD371 CD115 GMP 的人早期中性粒细胞祖细胞的早期分化过程。这些过程在体外和体内衍生细胞中通过单细胞 RNA 测序进行了阐明。随后，我们使用α-硫辛酸 (ALA) 诱导的中性粒细胞缺乏模型鉴定出转录因子 ELK1 对于人类中性粒细胞谱系分化是必需的。最后，我们还揭示了长 ELK1 和短 ELK1 通过 SF3B1 平衡在中性粒细胞祖细胞分化过程中的差异作用。总之，我们发现了 ALA 在调节中性粒细胞谱系特化中的新功能，并鉴定出 SF3B1-ELK 轴调节 CD371 CD115 GMP 向人类中性粒细胞祖细胞的分化。
