Pre-Setting the Metabolic Pathways During Stem Cell Programming

The role of metabolism has traditionally been viewed solely as a pathway for energy production without any influence on cell fate determination. However, in 1926, Otto Warburg reported that cancer cells exhibit high glucose consumption, popularly known as the Warburg effect. Cells orchestrate their metabolic program to meet their functional needs. All proliferating cells, from tumor cells to pluripotent cells such as naive, primed, and induced pluripotent cells, activated T and B cells shunt glucose to glycolysis and inhibit oxidative phosphorylation. This tailoring utilizes glucose in a biosynthetic pathway to generate metabolites that help in biomass production during cell division. Differentiated cells, designed to perform functional work, need more energy and hence follow oxidative phosphorylation to produce 36 molecules of adenosine triphosphate (ATP). Several studies have confirmed the direct link between glycolysis and cell proliferation. Pyruvate kinase M2 (PKM2) isoform enables dividing cells to adapt to a glycolytic lifestyle and promote anabolism. Stem cell transcription factors such as OCT4 and c-Myc promote glycolysis, while the AMP/ATP ratio functions as a sensor to determine the choice between glycolysis and oxidative phosphorylation. Tumor cells adhere to their own metabolic cues to promote tumorigenesis. Additionally, metabolic reprogramming produces acetyl CoA, lactyl residues, and S-adenosyl methionine, which contribute to epigenetic modifications and facilitate nuclear reprogramming.