BHB promotes the proliferation of neural stem cells by activating the Erk1/2- MAPK pathway and changing histone modification patterns

Neural stem cells (NSCs) have the ability to proliferate and differentiate into neurons, astrocytes, oligodendrocytes and some other types of cells, which were used in therapies for multiple neural system disorders. However, the efficacy of NSCs is limited by their short lifespan. Therefore, promoting the proliferation of NSCs is one of the key bottlenecks in their use for transplantation and treatment. According to our research, β-hydroxybutyrate (BHB) promoted cell cycle progression, thereby enhancing the proliferation of both primary NSCs and neural progenitor cell line C17.2. The BHB receptors GPR41 and GPR109A were found to mediate this effect by activating the Erk1/2 pathway. Furthermore, the key transcription factors regulating NSC proliferation, Pax6 and Sox2, were also upregulated by BHB via increased histone trimethylation and acetylation levels in their promoters. In conclusion, BHB enhanced the proliferation of NSCs through a receptor-dependent pathway. At same time, epigenetic modification also plays a role in this process.