Elevated Exogenous Pyruvate Potentiates Mesodermal Differentiation through Metabolic Modulation and AMPK/mTOR Pathway in Human Embryonic Stem Cells.
Pyruvate is a key metabolite in glycolysis and the tricarboxylic acid (TCA) cycle. Exogenous pyruvate modulates metabolism, provides cellular protection, and is essential for the maintenance of human preimplantation embryos and human embryonic stem cells (hESCs). However, little is known about how pyruvate contributes to cell-fate determination during epiblast stage. In this study, we used hESCs as a model to demonstrate that elevated exogenous pyruvate shifts metabolic balance toward oxidative phosphorylation in both maintenance and differentiation conditions. During differentiation, pyruvate potentiates mesoderm and endoderm lineage specification. Pyruvate production and its mitochondrial metabolism are required in BMP4-induced mesoderm differentiation. However, the TCA-cycle metabolites do not have the same effect as pyruvate on differentiation. Further study shows that pyruvate increases AMP/ATP ratio, activates AMPK, and modulates the mTOR pathway to enhance mesoderm differentiation. This study reveals that exogenous pyruvate not only controls metabolism but also modulates signaling pathways in hESC differentiation.
['Song|Chengcheng|C|', 'Xu|Faxiang|F|', 'Ren|Zhili|Z|', 'Zhang|Yumeng|Y|', 'Meng|Ya|Y|', 'Yang|Yiqi|Y|', 'Lingadahalli|Shreyas|S|', 'Cheung|Edwin|E|', 'Li|Gang|G|', 'Liu|Weiwei|W|', 'Wan|Jianbo|J|', 'Zhao|Yang|Y|', 'Chen|Guokai|G|']
D055372:AMP-Activated Protein Kinases D055415:Bone Morphogenetic Protein 4 D002454:Cell Differentiation D019070:Cell Lineage D002952:Citric Acid Cycle D004707:Endoderm D018398:Homeodomain Proteins D000066449:Human Embryonic Stem Cells D006801:Humans D008648:Mesoderm D008928:Mitochondria D010085:Oxidative Phosphorylation D019289:Pyruvic Acid D015398:Signal Transduction D020825:T-Box Domain Proteins D058570:TOR Serine-Threonine Kinases D015854:Up-Regulation
pyruvate mesoderm differentiation metabolism AMPK glycolysis hESCs BMP4 TCA cycle WNT