Metabolic oxidation regulates embryonic stem cell differentiation.
Metabolites offer an important unexplored complementary approach to understanding the pluripotency of stem cells. Using MS-based metabolomics, we show that embryonic stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. By monitoring the reduced and oxidized glutathione ratio as well as ascorbic acid levels, we demonstrate that the stem cell redox status is regulated during differentiation. On the basis of the oxidative biochemistry of the unsaturated metabolites, we experimentally manipulated specific pathways in embryonic stem cells while monitoring the effects on differentiation. Inhibition of the eicosanoid signaling pathway promoted pluripotency and maintained levels of unsaturated fatty acids. In contrast, downstream oxidized metabolites (for example, neuroprotectin D1) and substrates of pro-oxidative reactions (for example, acyl-carnitines), promoted neuronal and cardiac differentiation. We postulate that the highly unsaturated metabolome sustained by stem cells allows them to differentiate in response to in vivo oxidative processes such as inflammation.
Yanes
Oscar
O
Department of Molecular Biology and Scripps Center for Mass Spectrometry, The Scripps Research Institute, La Jolla, California, USA.
Clark
Julie
J
Wong
Diana M
DM
Patti
Gary J
GJ
Sánchez-Ruiz
Antonio
A
Benton
H Paul
HP
Trauger
Sunia A
SA
Desponts
Caroline
C
Ding
Sheng
S
Siuzdak
Gary
G
D000596:Amino Acids / Q000378:metabolism; D002264:Carboxylic Acids / Q000378:metabolism; D002331:Carnitine / Q000378:metabolism; D002454:Cell Differentiation; D015777:Eicosanoids / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D010641:Phenotype; D020543:Proteome / Q000378:metabolism; D012984:Software; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
D000596:Amino Acids; D002264:Carboxylic Acids; D015777:Eicosanoids; D020543:Proteome; D005978:Glutathione; D002331:Carnitine