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Bivalent Metabolism Maintains hESC Pluripotency

Nicotinamide adenine dinucleotide (NAD+) induces an intermediate state of naivety in human embryonic stem cells (hESCs) characterized by a shift from glycolytic to oxidative metabolism, increased self‐renewal, and epigenetic alterations. Conversely, inhibition of the malate aspartate shuttle (MAS), which recycles NAD+, causes a dramatic loss of oxidative metabolism and pluripotency marker expression. Now, a new study from the laboratory of David K. Gardner (University of Melbourne, Parkville, VIC, Australia) reveals a vital role for MAS in regulating the metabolic state of hESCs. Collectively, the findings reported recently in STEM CELLS indicate that NAD+ availability is not only regulated by MAS but also that NAD+ is critical to the maintenance of self‐renewal in hESCs and a potential regulator of the pluripotent state.