Nicotinamide adenine dinucleotide induces a bivalent metabolism and maintains pluripotency in human embryonic stem cells. (4th February 2020)

• Record Type: Journal Article
• Authors: Lees, Jarmon G.; Gardner, David K.; Harvey, Alexandra J.
• Is Part Of: Stem cells. Volume 38:Number 5(2020)
• Page Start: 624
• Page End: 638
• Publication Date: 2020-02-04
• Subjects: glycolysis -- malate aspartate shuttle -- mitochondria -- naïve -- nicotinamide adenine dinucleotide -- pluripotent; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.3152
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Nicotinamide adenine dinucleotide (NAD + ) and its precursor metabolites are emerging as important regulators of both cell metabolism and cell state. Interestingly, the role of NAD + in human embryonic stem cell (hESC) metabolism and the regulation of pluripotent cell state is unresolved. Here we show that NAD + simultaneously increases hESC mitochondrial oxidative metabolism and partially suppresses glycolysis and stimulates amino acid turnover, doubling the consumption of glutamine. Concurrent with this metabolic remodeling, NAD + increases hESC pluripotent marker expression and proliferation, inhibits BMP4‐induced differentiation and reduces global histone 3 lysine 27 trimethylation, plausibly inducing an intermediate naïve‐to‐primed bivalent metabolism and pluripotent state. Furthermore, maintenance of NAD + recycling via malate aspartate shuttle activity is identified as an absolute requirement for hESC self‐renewal, responsible for 80% of the oxidative capacity of hESC mitochondria. Our findings implicate NAD + in the regulation of cell state, suggesting that the hESC pluripotent state is dependent upon cellular NAD + . Abstract : Nicotinamide adenine dinucleotide induces an intermediate state of naivety in human embryonic stem cells characterized by a shift in metabolism from glycolytic to more oxidative, increased glutamine consumption, increased pluripotency and self‐renewal, and a reduction in global histone 3 lysine 27 trimethylation.