Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 37, Issue 19, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00086-17
Keywords
NRF2; hematopoietic stem cells; cell cycle; proliferation; differentiation
Categories
Funding
- JSPS KAKENHI [15H04692, 16K15228, 15K18999]
- Uehara Memorial Foundation
- Mitsubishi Foundation
- Naito Foundation
- Princess Takamatsu Cancer Research Fund [15-24728]
- IDAC Tohoku University
- GSK Japan research grant
- Core Research for Evolutional Science and Technology program of AMED
- Grants-in-Aid for Scientific Research [17K19508, 17F17116, 16K15228, 26111002, 15H04692, 15K18999] Funding Source: KAKEN
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Tissue stem cells are maintained in quiescence under physiological conditions but proliferate and differentiate to replenish mature cells under stressed conditions. The KEAP1-NRF2 system plays an essential role in stress response and cytoprotection against redox disturbance. To clarify the role of the KEAP1-NRF2 system in tissue stem cells, we focused on hematopoiesis in this study and used Keap1-deficient mice to examine the effects of persistent activation of NRF2 on long-term hematopoietic stem cells (LT-HSCs). We found that persistent activation of NRF2 due to Keap1 deficiency did not change the number of LT-HSCs but reduced their quiescence in steady-state hematopoiesis. During hematopoietic regeneration after bone marrow (BM) transplantation, persistent activation of NRF2 reduced the BM reconstitution capacity of LT-HSCs, suggesting that NRF2 reduces the quiescence of LT-HSCs and promotes their differentiation, leading to eventual exhaustion. Transient activation of NRF2 by an electrophilic reagent also promotes the entry of LT-HSCs into the cell cycle. Taken together, our findings show that NRF2 drives the cell cycle entry and differentiation of LT-HSCs at the expense of their quiescence and maintenance, an effect that appears to be beneficial for prompt recovery from blood loss. We propose that the appropriate control of NRF2 activity by KEAP1 is essential for maintaining HSCs and guarantees their stress-induced regenerative response.
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