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) 分化为中性粒细胞和单核细胞。最近，已经使用一系列表面标记物在小鼠和人类中鉴定出单潜能中性粒细胞祖细胞。然而，人类 GMP 如何作用于中性粒细胞祖细胞以及决定命运的调节机制仍未完全了解。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。使用这种中性粒细胞缺乏模型，我们确定了从 CD371 ⁺ CD115 开始的中性粒细胞祖细胞承诺过程^–GMPs 由 CD34 和 CD15 定义，并发现由 RNA 剪接和 rRNA 生物发生产生的关键信号调节源自 CD371 ⁺ CD115 ^– GMPs 的人类早期中性粒细胞祖细胞的早期承诺过程。通过体外和体内的单细胞 RNA 测序阐明了这些过程衍生细胞。随后，我们使用 α-硫辛酸 (ALA) 诱导的中性粒细胞缺乏模型确定了转录因子 ELK1 对人类中性粒细胞谱系定型至关重要。最后，我们还揭示了由 SF3B1 平衡的长 ELK1 和短 ELK1 在中性粒细胞祖细胞的承诺过程中的不同作用。总之，我们发现了 ALA 在调节中性粒细胞谱系规范中的新功能，并确定 SF3B1-ELK 轴调节来自 CD371 ⁺ CD115 ^- GMP 的人类中性粒细胞祖细胞的承诺。