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Review
. 2024 Jan 11:11:1328522.
doi: 10.3389/fcell.2023.1328522. eCollection 2023.

Metabolic control of induced pluripotency

Sergey A Sinenko  1 , Alexey N Tomilin  1
Affiliations
Review

Metabolic control of induced pluripotency

Sergey A Sinenko et al. Front Cell Dev Biol. .

Abstract

Pluripotent stem cells of the mammalian epiblast and their cultured counterparts-embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs)-have the capacity to differentiate in all cell types of adult organisms. An artificial process of reactivation of the pluripotency program in terminally differentiated cells was established in 2006, which allowed for the generation of induced pluripotent stem cells (iPSCs). This iPSC technology has become an invaluable tool in investigating the molecular mechanisms of human diseases and therapeutic drug development, and it also holds tremendous promise for iPSC applications in regenerative medicine. Since the process of induced reprogramming of differentiated cells to a pluripotent state was discovered, many questions about the molecular mechanisms involved in this process have been clarified. Studies conducted over the past 2 decades have established that metabolic pathways and retrograde mitochondrial signals are involved in the regulation of various aspects of stem cell biology, including differentiation, pluripotency acquisition, and maintenance. During the reprogramming process, cells undergo major transformations, progressing through three distinct stages that are regulated by different signaling pathways, transcription factor networks, and inputs from metabolic pathways. Among the main metabolic features of this process, representing a switch from the dominance of oxidative phosphorylation to aerobic glycolysis and anabolic processes, are many critical stage-specific metabolic signals that control the path of differentiated cells toward a pluripotent state. In this review, we discuss the achievements in the current understanding of the molecular mechanisms of processes controlled by metabolic pathways, and vice versa, during the reprogramming process.

Keywords: cellular reprogramming; embryonic stem cells (ESCs); glycolysis; induced pluripotent stem cells (iPSCs); mitochondria; oxidative phosphorylation (OxPhos); pluripotency; reactive oxygen species (ROS).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Summary table of molecular and metabolic characteristics of cells at different stages of reprogramming toward pluripotency state, mediated by ectopic expression of TFs Oct4, Sox2, Klf4, and c-Myc (OSKM). The process occurs during the sequential initiation, maturation, and stabilization stages, all taking place within a 12-day time interval. Critical factors, the functions of which are required for the reprogramming process, are indicated in regular font. The dominance of factors or processes is marked in bold. Functions and factors that are downregulated during reprogramming are marked with a suppression sign (⊥); see details in the text and abbreviations.
FIGURE 2
FIGURE 2
Schematic representation of the major metabolic pathways involved in regulating the process of reprogramming differentiated cells toward a pluripotent state. Metabolic pathways are highlighted in boxes, and key metabolic enzymes and metabolites involved in the regulation of reprogramming are noted in blue and purple rectangles, respectively. Transcription factors participating in positive and negative regulation of certain metabolic pathways are placed next to each of these pathways and depicted in green and brown, respectively. (I-III)—indicated for the initiation (I), maturation (II), stabilization (III) stages of the reprogramming process.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The work was supported by the Russian Science Foundation Grant No. 21-14-00369.