Stress hematopoiesis regualted by C/EBPbeta transcription factor

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K08354
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tokyo University of Pharmacy and Life Science (2020-2021); Kyoto University (2018-2019)
• Principal Investigator: HIRAI HIDEYO 東京薬科大学, 生命科学部, 教授 (50315933)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 造血幹細胞 / 生体防御 / 分化 / 転写因子

Outline of Final Research Achievements

The transcription factor C/EBPβ is required for stress-induced granulopoiesis which requires both proliferation and differentiation of hematopoietic stem/progenitor cells (HSPCs). In this study, we focused on the three isoforms of C/EBPβ. Under stress conditions, Cebpb-/- HSPCs exhibited impaired cell cycle activation and myeloid differentiation at the early and late phases of regeneration, respectively. Novel flow cytometric analysis revealed that among the three isoforms of C/EBPβ, LIP was upregulated in HSCs prior to LAP/LAP* during regeneration. Early upregulation of LIP promoted cell cycle entry of HSCs and expanded HSPCs pool. Subsequent myeloid differentiation of amplified HSPCs was mediated by LAP/LAP*, which were upregulated at a later phase of regeneration. Collectively, our findings show that stress-induced sequential upregulation of C/EBPβ isoforms is critical for fine-tuning the proliferation and differentiation of regenerating HSPCs.

Free Research Field

造血制御

Academic Significance and Societal Importance of the Research Achievements

今回の研究で、転写因子C/EBPβのアイソフォームの発現を単一細胞レベルで解析できる実験系の確立とともに、骨髄球系細胞の増殖と分化の両方が必要とされるストレス負荷時の造血幹細胞制御におけるC/EBPβの作用メカニズムの一端をはじめて明らかにすることができた。今後、個々のアイソフォームが欠損するようなマウスの解析などによって知見を集積し、ストレス造血の制御機構の全貌解明と、それが破綻した状態としての造血器悪性腫瘍の病態解明、体外での骨髄球系細胞の産生と細胞療法への応用などへの展開が考えられる。