Metabolic Regulation in Pluripotent Stem Cells during Reprogramming and Self-Renewal

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell stem cell (Impact Factor: 22.27). 11/2012; 11(5):589-95. DOI: 10.1016/j.stem.2012.10.005
Source: PubMed


Small, rapidly dividing pluripotent stem cells (PSCs) have unique energetic and biosynthetic demands compared with typically larger, quiescent differentiated cells. Shifts between glycolysis and oxidative phosphorylation with PSC differentiation or reprogramming to pluripotency are accompanied by changes in cell cycle, biomass, metabolite levels, and redox state. PSC and cancer cell metabolism are overtly similar, with metabolite levels influencing epigenetic/genetic programs. Here, we discuss the emerging roles for metabolism in PSC self-renewal, differentiation, and reprogramming.

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    • "For example, certain cells of solid tumors can produce ATP under glucose deprivation conditions [14]. Additionally, certain cancer cell lines can efficiently produce higher than normal amounts of ATP (possibly by developing alternative pathways) although mitochondrial performance has been compromised [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]. It is well-known that in the case of prolonged mitochondrial dysfunction the nuclear transcriptional activity is drastically changed as cells acquire an alternative metabolic profile and an oncogenic phenotype [12]. "
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    ABSTRACT: Recent evidence shows that mitochondria regulate nuclear transcriptional activity both in normal and cell stress conditions, known as retrograde signaling. Under normal mitochondrial function, retrograde signaling is associated with mitochondrial biogenesis, normal cell phenotype and metabolic profile. In contrast, mitochondrial dysfunction leads to abnormal (oncogenic) cell phenotype and altered bio-energetic profile (nucleus reprogramming). Despite intense research efforts, a concrete mechanism through which mitochondria determine the group of genes expressed by the nucleus is still missing. The present paper proposes a novel hypothesis regarding retrograde signaling. More specifically, it reveals the mitochondrial membrane potential (MMP) and the accompanied strong electromagnetic field (EF) as key regulatory factors of nuclear activity. Mitochondrial emitted EFs extend in long distance and affect the function of nuclear membrane receptors. Depending on their frequencies, EFs can directly activate or deactivate different groups of nuclear receptors and so determine nuclear gene expression. One of the key features of the above hypothesis is that nuclear membrane receptors, besides their own endogenous or chemical ligands (hormones, lipids, etc.), can also be activated by electromagnetic signals. Moreover, normal MMP values (about -140mV) are associated with the production of high ATP quantities and small levels of reactive oxygen species (ROS) while the hyperpolarization observed in all cancer cell types leads to a dramatic fall in ATP production and an analogous increase in ROS. The diminished ATP and increased ROS production negatively affect the function of all cellular systems including nucleus. Restoration of mitochondrial function, which is characterized by the fluctuation of MMP and EF values within a certain (normal) range, is proposed as a necessary condition for normal nuclear function and cancer therapy.
    Medical Hypotheses 10/2015; 85(6). DOI:10.1016/j.mehy.2015.10.004 · 1.07 Impact Factor
    • "In line with this, the protection of mitochondrial function with a variety of mitochondria-protective compounds attenuates inflammation-associated loss of Dcx 1 cells both in vivo and in vitro (Voloboueva et al., 2010). NSC differentiation involves a strong increase in mitochondrial oxidative metabolism (Wang et al., 2010; Zhang et al., 2012). Although increased mitochondrial metabolism is essential for cellular energetics, it can also result in excessive reactive oxygen species (ROS) production, eventually leading to damage of mitochondrial DNA and compromised mitochondrial function. "
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    ABSTRACT: Recent studies have demonstrated that neural stem cell (NSC) culture at physiologically normoxic conditions (2-5% O2 ) is advantageous in terms of neuronal differentiation and survival. Neuronal differentiation is accompanied by a remarkable shift to mitochondrial oxidative metabolism compared with preferentially glycolytic metabolism of proliferating cells. However, metabolic changes induced by growth in a normoxic (5%) O2 culture environment in NSCs have been minimally explored. This study demonstrates that culturing under 5% O2 conditions results in higher levels of mitochondrial oxidative metabolism, decreased glycolysis, and reduced levels of reactive oxygen species in NSC cultures. Inflammation is one of the major environmental factors limiting postinjury NSC neuronal differentiation and survival. Our results show that NSCs differentiated under 5% O2 conditions possess better resistance to in vitro inflammatory injury compared with those exposed to 20% O2 . The present work demonstrates that lower, more physiologically normal O2 levels support metabolic changes induced during NSC neuronal differentiation and provide increased resistance to inflammatory injury, thus highlighting O2 tension as an important determinant of cell fate and survival in various stem cell therapies. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 07/2015; 93(11). DOI:10.1002/jnr.23615 · 2.59 Impact Factor
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    • "Whereas the transcriptional and epigenetic dynamics have been extensively documented (Buganim et al., 2012; O'Malley et al., 2013; Polo et al., 2012; Theunissen and Jaenisch, 2014), temporal changes in metabolic states during the induction of pluripotency remain largely unknown. Distinct from somatic cells, pluripotent stem cells have unique metabolic pathways (Zhang et al., 2012), which influence their cellular behavior and epigenetic status (Lu and Thompson, 2012; Shyh-Chang et al., 2013a, 2013b). Indeed, factors involved in metabolic functions such as mitochondrial proteins are among the first to be upregulated in cells undergoing reprogramming (Hansson et al., 2012). "
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    ABSTRACT: Cell metabolism is adaptive to extrinsic demands; however, the intrinsic metabolic demands that drive the induced pluripotent stem cell (iPSC) program remain unclear. Although glycolysis increases throughout the reprogramming process, we show that the estrogen-related nuclear receptors (ERRα and ERRγ) and their partnered co-factors PGC-1α and PGC-1β are transiently induced at an early stage, resulting in a burst of oxidative phosphorylation (OXPHOS) activity. Upregulation of ERRα or ERRγ is required for the OXPHOS burst in both human and mouse cells, respectively, as well as iPSC generation itself. Failure to induce this metabolic switch collapses the reprogramming process. Furthermore, we identify a rare pool of Sca1(-)/CD34(-) sortable cells that is highly enriched in bona fide reprogramming progenitors. Transcriptional profiling confirmed that these progenitors are ERRγ and PGC-1β positive and have undergone extensive metabolic reprogramming. These studies characterize a previously unrecognized, ERR-dependent metabolic gate prior to establishment of induced pluripotency. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell stem cell 04/2015; 16(5). DOI:10.1016/j.stem.2015.03.001 · 22.27 Impact Factor
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