Modifying ESC media directs stem cell development in the lab.

Scripps Research Institute researchers claim that the differentiation of embryonic stem cells into specific mature cell types is dependent on that activation of oxidative pathways that modify their largely unsaturated populations of metabolites.

They found that in undifferentiated stem cells, the high degree of metabolite unsaturation makes the molecules reactive and susceptible to oxygenation and hydrogenation reactions, conferring them with what may be interpreted as a type of “chemical plasticity.” Levels of unsaturated metabolites dropped in parallel with cell differentiation, suggesting that modification of these molecules is involved in the process of directing cell maturation.

The results are published in Nature Chemical Biology, in a paper titled, “Metabolic oxidation regulates embryonic stem cell differentiation.”

Studies into stem cell gene-expression, epigenetic regulation, and protein-expression patterns have provided valuable insights into stem cell biology, report Scripps research associate professor Sheng Ding and colleagues. However, the molecular framework that controls the balance between pluripotency and stem cell differentiation is still not fully understood.

To address this issue, the researchers took a different tack, and probed stem cell metabolomics; essentially the metabolic complement of functional genomics. In what they claim is the first study to characterize stem cells with an untargeted metabolomics approach, the team used liquid chromatography–electrospray ionization–time of flight MS (LC-ESI-TOF-MS) to characterize the metabolic signatures of two different lines of mouse embryonic stem cells that have greater than 99% homogeneity. They then analyzed their differentiated progenies when more than 80% of the cells were neurons and more than 70% were cardiomyocytes

They found that embryonic stem cells are characterized by abundant metabolites with highly unsaturated structures, and that levels of these unsaturated molecules decrease upon the cells’ differentiation. By monitoring the reduced and oxidized glutathione ratio as well as ascorbic acid levels, they confirmed that stem cell redox status is regulated during differentiation

The researchers also managed to either prevent or trigger embryonic stem cell differentiation into mature heart and nerve cells by blocking oxidation or adding oxidized metabolites. When they inhibited inhibition of 5Ä and 6Ä desaturases by curcumin and sesamin, differentiation was delayed. Conversely, when the team supplemented the embryonic stem cell media with essential, naturally occurring metabolites associated with oxidative metabolism in mitochondria, there was a substantial increase in neuronal and cardiac differentiation.

“This study reveals an astounding cellular strategy,” claims lead author, research associate Oscar Yanes, Ph.D. “The capacity of embryonic stem cells to generate a whole spectrum of cell types characteristic of different tissues is mirrored at the metabolic level.”

“We were not expecting these results,” admits co-author, Gary Siuzdak, Ph.D., senior director of the Scripps Research Center for Mass Spectrometry. “Although in retrospect it makes sense that stem cells (which can form almost any cell) have metabolites that are chemically flexible.”

The findings may also have implications for our understanding of natural mechanisms of tissue repair, the Scripps team suggests. “Our results raise the noteworthy possibility that specific endogenous inflammatory mediators might regulate the regenerative properties of stem cells,” they write.

“This data suggest that specific molecular responses to injury and inflammation may regulate the proliferation and differentiation of stem cells; this may lead to the exploration of new avenues in understanding properties associated with regeneration. Further investigation will determine the mechanisms by which proinflammatory and proresolving endogenous metabolites activate proliferation and differentiation of quiescent stem or progenitor cells in response to tissue repair or wound healing.”

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