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Frontiers in Biology

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Front. Biol.    2016, Vol. 11 Issue (5) : 355-365    https://doi.org/10.1007/s11515-016-1417-z
REVIEW
Metabolism of pluripotent stem cells
Liang Hu,Edward Trope,Qi-Long Ying()
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Abstract

BACKGROUND: Recently, growing attention has been directed toward stem cell metabolism, with the key observation that metabolism not only fuels the proper functioning of stem cells but also regulates the fate of these cells. There seems to be a clear link between the self-renewal of pluripotent stem cells (PSCs), in which cells proliferate indefinitely without differentiation, and the activity of specific metabolic pathways. The unique metabolism in PSCs plays an important role in maintaining pluripotency by regulating signaling pathways and resetting the epigenome.

OBJECTIVE: To review the most recent publications concerning the metabolism of pluripotent stem cells and the role of metabolism in PSC self-renewal and differentiation.

METHODS: A systematic literature search related to the metabolism of PSCs was conducted in databases including Medline, Embase, and Web of Science. The search was performed without language restrictions on all papers published before May 2016. The following keywords were used: “metabolism” combined with either “embryonic stem cell” or “epiblast stem cell.”

RESULTS: Hundreds of papers focusing specifically on the metabolism of pluripotent stem cells were uncovered and summarized.

CONCLUSION: Identifying the specific metabolic pathways involved in pluripotency maintenance is crucial for progress in the field of developmental biology and regenerative medicine. Additionally, better understanding of the metabolism in PSCs will facilitate the derivation and maintenance of authentic PSCs from species other than mouse, rat, and human.
Keywords metabolism      pluripotent stem cells      pluripotency      epigenetics     
Corresponding Author(s): Qi-Long Ying   
Online First Date: 13 September 2016    Issue Date: 04 November 2016
 Cite this article:   
Liang Hu,Edward Trope,Qi-Long Ying. Metabolism of pluripotent stem cells[J]. Front. Biol., 2016, 11(5): 355-365.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-016-1417-z
https://academic.hep.com.cn/fib/EN/Y2016/V11/I5/355
Fig.1  The metabolism of glucose in pluripotent stem cells (PSCs). In PSCs, glucose is sequentially catalyzed by multiple enzymes in the cytoplasm to become pyruvate via glycolysis, which can be further oxidized into CO2 in the mitochondrial tricarboxylic acid (TCA) cycle to generate large amounts of ATP through the process of oxidative phosphorylation (OXPHOS) . Pyruvate can also be reductively metabolized to lactate, which predominates in PSCs even under normal oxygen levels. In addition, the metabolism of glucose provides ample intermediates for macromolecule synthesis. For instance, glucose-6-phosphate, glyceraldehyde-3-phosphate, and dihydroxyacetone produced during glucose metabolism can be used to synthesize nucleotides, amino acids, and fatty acids, respectively. NAD: Oxidized nicotinamide adenine dinucleotide; NADH: reduced NAD.
Fig.2  The characteristic amino acid metabolism of PSCs. Under the “2i+LIF” condition, PSCs can convert glutamine into glutamate, which is further rewired to generate a-ketoglutarate (aKG) and thus more aKG-dependent demethylase, such as JmjC dioxygenease. JmjC contributes to pluripotency maintainence through demethylation of the repressive chromatin landscape. In addition, mouse embryonic stem cells (mESCs) are characterized by a unique threonine metabolism. Threonine dehydrogenase (Tdh) converts threonine into glycine and acetyl-CoA. Glycine is then used to produce a one-carbon pool to promote nucleotide synthesis and rapid proliferation of mESCs; Acetyl-coA joins the TCA cycle and feeds the bioenergetics and biosynthetics of mESCs. Furthermore, Tdh enhances the synthesis of S-adenosylmethionine (SAM), leading to a high ratio of SAM/S-adenosyl homocysteine (SAH) and high levels of H3K4me3, an active transcriptional chromatin marker. In contrast, human embryonic stem cells (hESCs) rely on methionine rather than threonine since Tdh is a pseudogene in human. Similar to threonine, methionine is an important source of SAM. Methionine deprivation lowers SAM levels and induces the demethylation of H3K4me3. THF: tetrahydrofolate.
Fig.3  The epigenetic connection between metabolism and pluripotency of PSCs. Cellular metabolism provides ample substrates and co-factors for epigenetic regulation of the genome of PSCs and contributes to pluripotency maintenance. Glucose-derived acetyl-CoA is an important substrate for histone acetylation mediated by histone acetyltransferases (HAT). SAM converted from threonine and methionine is the essential methyl donor for histone methyltransferase (HMT) to maintain proper levels of H3K4me3. In addition, a-ketoglutarate (aKG) from glutamine metabolism activates Jmjd3, an aKG-dependent demethylase, and triggers the demythelyation of repressive chromatin markers. Also, Vitamin C promotes the demethylation of repressive histone markers by enhancing the activity of Tet and JmjC demethylases.
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