2. Academic Validation
  3. Dissecting the process of human neutrophil lineage determination by using alpha-lipoic acid inducing neutrophil deficiency model

Dissecting the process of human neutrophil lineage determination by using alpha-lipoic acid inducing neutrophil deficiency model

  • Redox Biol. 2022 Aug;54:102392. doi: 10.1016/j.redox.2022.102392.
Yong Dong 1,  Yimeng Zhang 2,  Yongping Zhang 3,  Xu Pan 2,  Ju Bai 2,  Yijin Chen 2,  Ya Zhou 2,  Zhenyang Lai 4,  Qiang Chen 5,  Shaoyan Hu 3,  Qiongxiu Zhou 2,  Yonggang Zhang 2,  Feng Ma 6
Affiliations

Affiliations

  • 1 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. Electronic address: dong_yong@ibt.pumc.edu.cn.
  • 2 Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Chengdu, China.
  • 3 Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou City, China.
  • 4 Sichuan Cord Blood Bank, Chengdu, China.
  • 5 Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Chengdu, China; Sichuan Cord Blood Bank, Chengdu, China.
  • 6 Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Chengdu, China. Electronic address: mafeng@ibt.pumc.edu.cn.
PMID: 35797799 DOI: 10.1016/j.redox.2022.102392
Abstract

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.

Keywords

Alpha-lipoic acid; ELK1; Monocytes; Neutrophils; RNA splicing; SF3B1.

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