Pluripotent stem cell energy metabolism: an update

doi:10.15252/embj.201490446

Review

. 2015 Jan 13;34(2):138-53.

doi: 10.15252/embj.201490446. Epub 2014 Dec 4.

Pluripotent stem cell energy metabolism: an update

Tara Teslaa¹, Michael A Teitell²

Affiliations

¹ Molecular Biology Institute, University of California, Los Angeles, CA, USA.
² Molecular Biology Institute, University of California, Los Angeles, CA, USA Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA Department of Bioengineering, University of California, Los Angeles, CA, USA Department of Pediatrics, University of California, Los Angeles, CA, USA California NanoSystems Institute, University of California, Los Angeles, CA, USA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA mteitell@mednet.ucla.edu.

PMID: 25476451
PMCID: PMC4337063
DOI: 10.15252/embj.201490446

Review

Pluripotent stem cell energy metabolism: an update

Tara Teslaa et al. EMBO J. 2015.

. 2015 Jan 13;34(2):138-53.

doi: 10.15252/embj.201490446. Epub 2014 Dec 4.

Authors

Tara Teslaa¹, Michael A Teitell²

Affiliations

¹ Molecular Biology Institute, University of California, Los Angeles, CA, USA.
² Molecular Biology Institute, University of California, Los Angeles, CA, USA Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA Department of Bioengineering, University of California, Los Angeles, CA, USA Department of Pediatrics, University of California, Los Angeles, CA, USA California NanoSystems Institute, University of California, Los Angeles, CA, USA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA mteitell@mednet.ucla.edu.

PMID: 25476451
PMCID: PMC4337063
DOI: 10.15252/embj.201490446

Abstract

Recent studies link changes in energy metabolism with the fate of pluripotent stem cells (PSCs). Safe use of PSC derivatives in regenerative medicine requires an enhanced understanding and control of factors that optimize in vitro reprogramming and differentiation protocols. Relative shifts in metabolism from naïve through "primed" pluripotent states to lineage-directed differentiation place variable demands on mitochondrial biogenesis and function for cell types with distinct energetic and biosynthetic requirements. In this context, mitochondrial respiration, network dynamics, TCA cycle function, and turnover all have the potential to influence reprogramming and differentiation outcomes. Shifts in cellular metabolism affect enzymes that control epigenetic configuration, which impacts chromatin reorganization and gene expression changes during reprogramming and differentiation. Induced PSCs (iPSCs) may have utility for modeling metabolic diseases caused by mutations in mitochondrial DNA, for which few disease models exist. Here, we explore key features of PSC energy metabolism research in mice and man and the impact this work is starting to have on our understanding of early development, disease modeling, and potential therapeutic applications.

Keywords: differentiation; epigenetics; metabolism; mitochondria; pluripotency.

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Figures

**Figure 1. Influence of energy metabolism on pluripotent status**
Naïve human pluripotent stem cells (hPSCs) show an increase in ATP production through oxidative phosphorylation (OXPHOS) compared to more mature, “primed” hPSCs. Primed hPSCs can be converted to the naïve state through ectopic expression of NANOG and KLF4, inhibition of the ERK pathway by two inhibitors (2i), and stimulation with human leukemia inhibitory factor (L) (Takashima *et al*, 2014). Alternatively, the naïve state can be induced with a cocktail of five inhibitors and growth factors Activin and hLIF (5i/L/A) (Theunissen Thorold *et al*, 2014). Somatic cells can be reprogrammed with OCT4, SOX2, KLF4, and c-MYC (OSKM). Fibroblasts are more oxidative than primed hPSCs. Factors that activate glycolysis and inhibit OXPHOS promote induced PSC (iPSC) reprogramming. Vitamin C enhances iPSC reprogramming as an antioxidant and as a cofactor for epigenetic enzymes. Rapamycin, an inhibitor of the mTOR pathway, also increases the efficiency of iPSC reprogramming. Withdrawal of methionine from hPSC culture, which is required to maintain DNA and histone methylation, promotes differentiation.

**Figure 2. Influence of metabolites on pluripotent stem cell epigenetics**
Intermediate metabolism sets and maintains levels of metabolites that serve as substrates or cofactors for epigenetic modifying enzymes. Uptake of threonine and methionine from the culture media is required to maintain S-adenosylmethionine (SAM) levels in mPSCs and hPSCs, respectively. SAM is a methyl donor for histone methyltransferases (HMT) and DNA methyltransferases (DNMTs). Vitamin C is a cofactor for the JMJC family of demethylases and TET methylcytosine dioxygenases (TET). Acetyl-CoA, a TCA cycle intermediate, is an acetyl group donor for histone acetyltransferases (HAT). NAD⁺, generated through glycolysis or by the electron transport chain (ETC), is a cofactor for the sirtuin (SIRT) family of deacetylases.

**Figure 3. Somatic cell reprogramming to pluripotency causes a mtDNA “bottleneck”**
mtDNA undergoes a genetic bottleneck, or reduction in copy number, during de-differentiation, similar to the mtDNA bottleneck that occurs during normal female germ line oogenesis. This reduction has an unresolved mechanism that results in a shift from a heteroplasmic toward a homoplasmic state with no clear preference for wild-type or mutant mtDNA. This shift does not occur during the continuous culturing of fibroblasts in which characteristic levels of heteroplasmy are maintained over time.

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The Force Is Strong with This One: Metabolism (Over)powers Stem Cell Fate.
Wei P, Dove KK, Bensard C, Schell JC, Rutter J. Wei P, et al. Trends Cell Biol. 2018 Jul;28(7):551-559. doi: 10.1016/j.tcb.2018.02.007. Epub 2018 Mar 16. Trends Cell Biol. 2018. PMID: 29555207 Free PMC article. Review.
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Betto RM, Diamante L, Perrera V, Audano M, Rapelli S, Lauria A, Incarnato D, Arboit M, Pedretti S, Rigoni G, Guerineau V, Touboul D, Stirparo GG, Lohoff T, Boroviak T, Grumati P, Soriano ME, Nichols J, Mitro N, Oliviero S, Martello G. Betto RM, et al. Nat Genet. 2021 Feb;53(2):215-229. doi: 10.1038/s41588-020-00770-2. Epub 2021 Feb 1. Nat Genet. 2021. PMID: 33526924 Free PMC article.
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References

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[1] Adamo A, Sese B, Boue S, Castano J, Paramonov I, Barrero MJ, Belmonte JCI. LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat Cell Biol. 2011;13:652–659. - PubMed

[2] Adamo A, Sese B, Boue S, Castano J, Paramonov I, Barrero MJ, Belmonte JCI. LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat Cell Biol. 2011;13:652–659. - PubMed

[3] Agrawal P, Reynolds J, Chew S, Lamba DA, Hughes RE. DEPTOR is a stemness factor that regulates pluripotency of embryonic stem cells. J Biol Chem. 2014;289:31818–31826. - PMC - PubMed

[4] Agrawal P, Reynolds J, Chew S, Lamba DA, Hughes RE. DEPTOR is a stemness factor that regulates pluripotency of embryonic stem cells. J Biol Chem. 2014;289:31818–31826. - PMC - PubMed

[5] Alavi MV, Bette S, Schimpf S, Schuettauf F, Schraermeyer U, Wehrl HF, Ruttiger L, Beck SC, Tonagel F, Pichler BJ, Knipper M, Peters T, Laufs J, Wissinger B. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain. 2007;130:1029–1042. - PubMed

[6] Alavi MV, Bette S, Schimpf S, Schuettauf F, Schraermeyer U, Wehrl HF, Ruttiger L, Beck SC, Tonagel F, Pichler BJ, Knipper M, Peters T, Laufs J, Wissinger B. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain. 2007;130:1029–1042. - PubMed

[7] Anokye-Danso F, Trivedi Chinmay M, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y, Yang W, Gruber Peter J, Epstein Jonathan A, Morrisey Edward E. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell. 2011;8:376–388. - PMC - PubMed

[8] Anokye-Danso F, Trivedi Chinmay M, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y, Yang W, Gruber Peter J, Epstein Jonathan A, Morrisey Edward E. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell. 2011;8:376–388. - PMC - PubMed

[9] Armstrong L, Tilgner K, Saretzki G, Atkinson SP, Stojkovic M, Moreno R, Przyborski S, Lako M. Human induced pluripotent stem cell lines show stress defense mechanisms and mitochondrial regulation similar to those of human embryonic stem cells. Stem Cells. 2010;28:661–673. - PubMed

[10] Armstrong L, Tilgner K, Saretzki G, Atkinson SP, Stojkovic M, Moreno R, Przyborski S, Lako M. Human induced pluripotent stem cell lines show stress defense mechanisms and mitochondrial regulation similar to those of human embryonic stem cells. Stem Cells. 2010;28:661–673. - PubMed

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Pluripotent stem cell energy metabolism: an update

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Pluripotent stem cell energy metabolism: an update

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