Significance: Stem cell activation and differentiation occur along changes in cellular metabolism. Metabolic transitions translate into changes in redox balance, cell signaling, and epigenetics, thereby regulating these processes. Metabolic transitions are key regulators of cell fate and exemplify the moonlighting nature of many metabolic enzymes and their associated metabolites. Recent Advances: Forkhead box O transcription factors (FOXOs) are bona fide regulators of cellular homeostasis. FOXOs are multitasking proteins able to regulate cell cycle, cellular metabolism, and redox state. Recent and ongoing research poses FOXOs as key factors in stem cell maintenance and differentiation in several tissues. Critical Issues: The multitasking nature of FOXOs and their tissue-specific expression patterns hinders to disclose a possible conserved mechanism of regulation of stem cell maintenance and differentiation. Moreover, cellular metabolism, cell signaling, and epigenetics establish complex regulatory interactions, which challenge the establishment of the causal/temporal nature of metabolic changes and stem cell activation and differentiation. Future Directions: The development of single-cell technologies and in vitro models able to reproduce the dynamics of stem cell differentiation are actively contributing to define the role of metabolism in this process. This knowledge is key to understanding and designing therapies for those pathologies where the balance between proliferation and differentiation is lost. Importantly, metabolic interventions could be applied to optimize stem cell cultures meant for therapeutical applications, such as transplantations, to treat autoimmune and degenerative disorders. Antioxid. Redox Signal. 34, 1004-1024.
Keywords: FOXO; differentiation; metabolism; mitochondria; stem cells.