Keap1‐Nrf2 system regulates cell fate determination of hematopoietic stem cells

Abstract

Nrf2 is a major transcriptional activator of cytoprotective genes against oxidative/electrophilic stress, and Keap1 negatively regulates Nrf2. Emerging works have also suggested a role for Nrf2 as a regulator of differentiation in various cells, but the contribution of Nrf2 to the differentiation of hematopoietic stem cells (HSCs) remains elusive. Clarifying this point is important to understand Nrf2 functions in the development and/or resolution of inflammation. Here, we established two transgenic reporter mouse lines that allowed us to examine Nrf2 expression precisely in HSCs. Nrf2 was abundantly transcribed in HSCs, but its activity was maintained at low levels due to the Keap1-mediated degradation of Nrf2 protein. When we characterized Keap1-deficient mice, their bone marrow cells showed enhanced granulocyte-monocyte differentiation at the expense of erythroid and lymphoid differentiation. Importantly, Keap1-null HSCs showed lower expression of erythroid and lymphoid genes than did control HSCs, suggesting granulocyte-monocyte lineage priming in Keap1-null HSCs. This abnormal lineage commitment was restored by a concomitant deletion of Nrf2, demonstrating the Nrf2-dependency of the skewing. Analysis of Nrf2-deficient mice revealed that the physiological level of Nrf2 is sufficient to contribute to the lineage commitment. This study unequivocally shows that the Keap1-Nrf2 system regulates the cell fate determination of HSCs.