Metabolic pathways have emerged as an intriguing means of influencing human embryonic stem cell (hESC) self-renewal and somatic cell reprogramming. HESCs are thought to favor a glycolytic state over oxidative metabolism, but the impact of nutrient availability on mitochondrial hESC metabolism is not well understood. Here we conducted <sup>13</sup>C/<sup>2</sup>H metabolic tracing and flux analysis to define the critical metabolic pathways supporting hESC expansion in different nutritional environments. Whereas glycolytic flux consistently supports hESC growth, chemically defined media strongly influence redox, glutamine, and lipid metabolism. Lipid deficiency in defined media dramatically reprograms pathways associated with fatty acid biosynthesis and NADPH regeneration, altering the redox state of cells and inducing dependency on the oxidative pentose phosphate pathway for self-renewal. Lipid supplementation mitigates this metabolic reprograming and increases oxidative metabolism. These results demonstrate that hESCs can self-renew in distinct metabolic states and highlight stresses associated with chemically defined hESC culture media.

Distinct metabolic states support pluripotent stem cell self-renewal

251st National Meeting (2016)

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