HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition

Abstract

The function of metabolic state in stemness is poorly understood. Mouse embryonicstem cells (ESC) and epiblast stem cells (EpiSC) are at distinct pluripotent statesrepresenting the inner cell mass (ICM) and epiblast embryos. Human embryonic stemcells (hESC) are similar to EpiSC stage. We now show a dramatic metabolic differencebetween these two stages. EpiSC/hESC are highly glycolytic, while ESC are bivalentin their energy production, dynamically switching from glycolysis to mitochondrialrespiration on demand. Despite having a more developed and expanding mitochondrialcontent, EpiSC/hESC have low mitochondrial respiratory capacity due to lowcytochrome c oxidase (COX) expression. Similarly, in vivo epiblastssuppress COX levels. These data reveal EpiSC/hESC functional similarity to theglycolytic phenotype in cancer (Warburg effect). We further show thathypoxia‐inducible factor 1α (HIF1α) is sufficient to drive ESC to aglycolytic Activin/Nodal‐dependent EpiSC‐like stage. This metabolic switch duringearly stem‐cell development may be deterministic.