NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells

Abstract

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.

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

“…LT HSC numbers in Vav1-Cre:Keap1 flox/flox did not increase; rather, the cells moved from a G 0 quiescent state into G1. This exit from quiescence was not observed in Vav1-Cre:Keap1 flox/flox ::Nrf2 −/− mice, demonstrating that the loss of quiescence was Nrf2 driven (60). Mechanistically, Nrf2-mediated loss of quiescence was a consequence of JAK-STAT signaling.…”

“…Vav1-Cre:Keap1 flox/flox mice were used to test the hypothesis that Nrf2 promotes HSC proliferation (60). Disruption of Keap1 exons 4 through 6 in LSK cells and LT HSCs elevated expression of Nrf2 and Nrf2 target genes.…”

“…Disruption of Keap1 exons 4 through 6 in LSK cells and LT HSCs elevated expression of Nrf2 and Nrf2 target genes. Similar to LSK cells in Mx-Cre;Keap1 flox/flox mice, there was a 1.4-fold enrichment of LSK cells in Vav1-Cre:Keap1 flox/flox mice (60). LT HSC numbers in Vav1-Cre:Keap1 flox/flox did not increase; rather, the cells moved from a G 0 quiescent state into G1.…”

“…This hypothesis was tested using a competitive transplantation assay. Indeed, LT HSCs obtained from Vav1-Cre:Keap1 flox/flox mice exhibited a deficiency in reconstitution capacity compared to control (60). These results were confirmed using Mx-Cre;Keap1 flox/flox mice treated with poly (I:C) or administered the Nrf2 activator 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im).…”

“…These results were confirmed using Mx-Cre;Keap1 flox/flox mice treated with poly (I:C) or administered the Nrf2 activator 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im). In these model systems it appears that prolonged activation of Nrf2 reduces LT HSC self-renewal and quiescence while driving differentiation, thereby diminishing the ability of LT HSCs to reconstitute irradiated bone marrow (60). The differences between the study of Kim et al (57) and that of Murakami et al (60) are not currently understood and require further investigation.…”