TY - JOUR
T1 - C/EBPβ isoforms sequentially regulate regenerating mouse hematopoietic stem/progenitor cells
AU - Sato, Atsushi
AU - Kamio, Naoka
AU - Yokota, Asumi
AU - Hayashi, Yoshihiro
AU - Tamura, Akihiro
AU - Miura, Yasuo
AU - Maekawa, Taira
AU - Hirai, Hideyo
N1 - Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020/7/28
Y1 - 2020/7/28
N2 - The transcription factor CCAAT enhancer-binding protein β (C/EBPβ) is required for stressinduced granulopoiesis at the level of hematopoietic stem/progenitor cells (HSPCs); however, its role and mechanisms of action in HSPCs are unknown. In this study, we assessed the regulation and functions of C/EBPβ in HSPCs, especially under stress conditions. After 5-fluorouracil treatment or bone marrow transplantation, Cebpb-/- HSPCs exhibited impaired cell-cycle activation and myeloid differentiation at the early and late phases of regeneration, respectively, whereas at steady state, Cebpb deficiency did not affect HSPCs. C/EBPβ was upregulated in response to hematopoietic stress, especially in CD150high long term-hematopoietic stem cells (LT-HSCs). Intracellular flow cytometric analysis that detected distinct domains of C/EBPβ revealed that, among the 3 isoforms of C/EBPβ, liver-enriched inhibitory protein (LIP) was upregulated in LT-HSCs prior to liver-enriched activating protein (LAP)/LAP∗ during regeneration. Early upregulation of LIP promoted cellcycle entry of LT-HSCs by positively regulating Myc and expanded the 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.
AB - The transcription factor CCAAT enhancer-binding protein β (C/EBPβ) is required for stressinduced granulopoiesis at the level of hematopoietic stem/progenitor cells (HSPCs); however, its role and mechanisms of action in HSPCs are unknown. In this study, we assessed the regulation and functions of C/EBPβ in HSPCs, especially under stress conditions. After 5-fluorouracil treatment or bone marrow transplantation, Cebpb-/- HSPCs exhibited impaired cell-cycle activation and myeloid differentiation at the early and late phases of regeneration, respectively, whereas at steady state, Cebpb deficiency did not affect HSPCs. C/EBPβ was upregulated in response to hematopoietic stress, especially in CD150high long term-hematopoietic stem cells (LT-HSCs). Intracellular flow cytometric analysis that detected distinct domains of C/EBPβ revealed that, among the 3 isoforms of C/EBPβ, liver-enriched inhibitory protein (LIP) was upregulated in LT-HSCs prior to liver-enriched activating protein (LAP)/LAP∗ during regeneration. Early upregulation of LIP promoted cellcycle entry of LT-HSCs by positively regulating Myc and expanded the 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.
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U2 - 10.1182/bloodadvances.2018022913
DO - 10.1182/bloodadvances.2018022913
M3 - Article
C2 - 32717031
AN - SCOPUS:85091970409
SN - 2473-9529
VL - 4
SP - 3343
EP - 3356
JO - Blood Advances
JF - Blood Advances
IS - 14
ER -