Metabolic Regulation in Pluripotent Stem Cells during Reprogramming and Self-Renewal
ABSTRACT 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.
- SourceAvailable from: Yasuyuki S Kida
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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). "
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 · 22.15 Impact Factor
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- "Furthermore, the somatic differentiated cells can be reprogrammed into induced pluripotent stem cells (iPSCs) through overexpression of a few transcription factors (TFs) or the metabolic switch (Ito and Suda, 2014; Takahashi and Yamanaka, 2006; Zhang et al., 2012). The primary functions of activated oncogenes and inactivated tumor suppressors may be to reprogram cellular metabolism and convert somatic cancer cells into pluripotent tumor-initiating cells (also called cancer stem cells [CSCs]) (Ward and Thompson, 2012; Zhang et al., 2012). Therefore, understanding how adult stem cells (particularly , somatic adult stem cells) are regulated is important for understanding tissue degeneration and tumorigenesis. "
ABSTRACT: The intestinal epithelium is the most rapidly self-renewing tissue in adult animals and maintained by intestinal stem cells (ISCs) in both Drosophila and mammals. To comprehensively identify genes and pathways that regulate ISC fates, we performed a genome-wide transgenic RNAi screen in adult Drosophila intestine and identified 405 genes that regulate ISC maintenance and lineage-specific differentiation. By integrating these genes into publicly available interaction databases, we further developed functional networks that regulate ISC self-renewal, ISC proliferation, ISC maintenance of diploid status, ISC survival, ISC-to-enterocyte (EC) lineage differentiation, and ISC-to-enteroendocrine (EE) lineage differentiation. By comparing regulators among ISCs, female germline stem cells, and neural stem cells, we found that factors related to basic stem cell cellular processes are commonly required in all stem cells, and stem-cell-specific, niche-related signals are required only in the unique stem cell type. Our findings provide valuable insights into stem cell maintenance and lineage-specific differentiation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Cell Reports 02/2015; 10(7). DOI:10.1016/j.celrep.2015.01.051 · 8.36 Impact Factor
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- "We examined how MYC contributes to the hallmark differences between normal neurons and malignant PNETS (Figure 4A). For example, MYC has been implicated in cancer-specific changes in glutamine metabolism and mitochondrial biology (Gao et al., 2009; Zhang et al., 2012). However , we saw only modest or no difference in expression of the glutamine transporter (SLC1A5) or the glutaminase enzyme (GLS) between differentiated neurons and PNETs (Figures 4A– 4C; Figure S3A). "
ABSTRACT: The long-term risk of malignancy associated with stem cell therapies is a significant concern in the clinical application of this exciting technology. We report a cancer-selective strategy to enhance the safety of stem cell therapies. Briefly, using a cell engineering approach, we show that aggressive cancers derived from human or murine induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) are strikingly sensitive to temporary MYC blockade. On the other hand, differentiated tissues derived from human or mouse iPSCs can readily tolerate temporary MYC inactivation. In cancer cells, endogenous MYC is required to maintain the metabolic and epigenetic functions of the embryonic and cancer-specific pyruvate kinase M2 isoform (PKM2). In summary, our results implicate PKM2 in cancer's increased MYC dependence and indicate dominant MYC inhibition as a cancer-selective fail-safe for stem cell therapies.Cell Reports 09/2014; 8(6). DOI:10.1016/j.celrep.2014.08.039 · 8.36 Impact Factor