Octamer-Binding Transcription Factor 4 Inhibits HSC Functions via the NF-κB Signaling Pathway After 60Co Irradiation.

Abstract

High doses of radiation can cause irreversible bone marrow hematopoietic damage and even death. No effective strategies have been developed to protect against radiation effects in hematopoietic stem cells (HSCs). A total-body irradiation model was used to determine damage to HSCs. HSCs were sorted for transcriptome sequencing, and gene function analysis showed that Octamer-Binding Transcription Factor 4 (Oct4) increased significantly after irradiation. Oct4 deletion or inhibition of nuclear factor kappa-B (NF-κB) significantly reversed HSC apoptosis, promoted HSC colony formation, reduced cellular DNA damage, and promoted bone marrow regeneration after irradiation. ChIP assays showed that Oct4 binds to the IκB kinase (IKK) promoter region and increases the level of IKK. Overexpression of Oct4 significantly increased the entry of NF-κB into the nucleus after irradiation. NF-κB activators reversed the protective roles of knocking out Oct4. In vivo, the knockout of Oct4 and inhibition of NF-κB significantly improved the survival rate of mice after irradiation. We further found that the expression level of Oct4 decreased significantly in human leukemia cells, while the overexpression of Oct4 significantly increased the level of apoptosis in leukemia cells after irradiation. This study demonstrated a novel role of Oct4 in mediating apoptosis of HSCs after irradiation through the NF-κB pathway, providing an important biomedical strategy for the functional protection of HSCs in bone marrow after irradiation.