Metabolome Profiling of Partial and Fully Reprogrammed Induced Pluripotent Stem Cells

Park, Soon‐Jung; Lee, Sang A; Prasain, Nutan; Bae, Daekyeong; Kang, Hyun Seo; Ha, Tae-Won; Kim, Jong Soo; Hong, Kee-Jong; Mantel, Charlie; Moon, Sung; Broxmeyer, Hal E.; Lee, Man Ryul

doi:10.1089/scd.2016.0320

Cited by 28 publications

(19 citation statements)

References 26 publications

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“…Additional metabolic analyses, and the inclusion of additional lines, would further elucidate the extent of metabolic memory retention by iPS cells. Recently, Park et al [ 51 ] reported significant differences in mitochondrial activity and specific metabolite levels in partially reprogrammed iPS cells, relative to fully reprogrammed iPS cells. In addition, Prigione et al [ 19 ] documented the acquisition of mtDNA mutations in human iPS cell lines not present in the parental cell line following reprogramming, while mouse iPS cells show altered mitochondrial replication upon differentiation relative to ES cells [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Physiological oxygen culture reveals retention of metabolic memory in human induced pluripotent stem cells

et al. 2018

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Reprogramming somatic cells to a pluripotent cell state (induced Pluripotent Stem (iPS) cells) requires reprogramming of metabolism to support cell proliferation and pluripotency, most notably changes in carbohydrate turnover that reflect a shift from oxidative to glycolytic metabolism. Some aspects of iPS cell metabolism differ from embryonic stem (ES) cells, which may reflect a parental cell memory, or be a consequence of the reprogramming process. In this study, we compared the metabolism of 3 human iPS cell lines to assess the fidelity of metabolic reprogramming. When challenged with reduced oxygen concentration, ES cells have been shown to modulate carbohydrate use in a predictably way. In the same model, 2 of 3 iPS cell lines failed to regulate carbohydrate metabolism. Oxygen is a well-characterized regulator of cell function and embryo viability, and an inability of iPS cells to modulate metabolism in response to oxygen may indicate poor metabolic fidelity. As metabolism is linked to the regulation of the epigenome, assessment of metabolic responses of iPS cells to physiological stimuli during characterization is warranted to ensure complete cell reprogramming and as a measure of cell quality.

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Section: Discussionmentioning

confidence: 99%

Physiological oxygen culture reveals retention of metabolic memory in human induced pluripotent stem cells

et al. 2018

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“…Although these differences exist, their functional impact on maintenance of pluripotency or differentiation capacity have not been examined. Partially reprogrammed cells, which are characterized by forming stable ESC-like colonies but not expressing endogenous OCT4, NANOG, SSEA4 and TRA-1-60, appear to have a distinct mitochondria and metabolic profile that are intermediate between fully reprogrammed iPSCs/ESCs and parental fibroblasts in terms of mitochondrial morphology and gene expression, and concentrations of glycolytic and OxPhos intermediates (Lee et al, 2016;Park et al, 2017). This insufficient repression of mitochondrial function and activation of glycolysis in partially reprogrammed cells can be rescued through microRNA 31 overexpression, which suppresses succinate dehydrogenase A activity to promote the transition from OxPhos to glycolysis and enhance reprogramming efficiency (Lee et al, 2016).…”

Section: Energy Metabolism Drives Acquisition Of Pluripotency Throughmentioning

confidence: 99%

Energy Metabolism Regulates Stem Cell Pluripotency

Tsogtbaatar

Landin

Minter-Dykhouse

et al. 2020

Front. Cell Dev. Biol.

162

138

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Pluripotent stem cells (PSCs) are characterized by their unique capacity for both unlimited self-renewal and their potential to differentiate to all cell lineages contained within the three primary germ layers. While once considered a distinct cellular state, it is becoming clear that pluripotency is in fact a continuum of cellular states, all capable of self-renewal and differentiation, yet with distinct metabolic, mitochondrial and epigenetic features dependent on gestational stage. In this review we focus on two of the most clearly defined states: "naïve" and "primed" PSCs. Like other rapidly dividing cells, PSCs have a high demand for anabolic precursors necessary to replicate their genome, cytoplasm and organelles, while concurrently consuming energy in the form of ATP. This requirement for both anabolic and catabolic processes sufficient to supply a highly adapted cell cycle in the context of reduced oxygen availability, distinguishes PSCs from their differentiated progeny. During early embryogenesis PSCs adapt their substrate preference to match the bioenergetic requirements of each specific developmental stage. This is reflected in different mitochondrial morphologies, membrane potentials, electron transport chain (ETC) compositions, and utilization of glycolysis. Additionally, metabolites produced in PSCs can directly influence epigenetic and transcriptional programs, which in turn can affect self-renewal characteristics. Thus, our understanding of the role of metabolism in PSC fate has expanded from anabolism and catabolism to include governance of the pluripotent epigenetic landscape. Understanding the roles of metabolism and the factors influencing metabolic pathways in naïve and primed pluripotent states provide a platform for understanding the drivers of cell fate during development. This review highlights the roles of the major metabolic pathways in the acquisition and maintenance of the different states of pluripotency.

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“…2,47,48 In humans, partially reprogrammed iPSCs resumed reprogramming by upregulation of KLF4, 49 and pre-iPSC-like cell lines were established as cancer stem cell lines. 50 Metabolome profiling demonstrated that human partially reprogrammed iPSCs shared only 74% similarly expressed metabolites with human ESCs, 51 indicating that transcriptome of partially reprogrammed stem cells is considerably different from that of ESCs. Therefore, establishment of iPSC lines makes no promise to establish stable lines of human partially reprogrammed iPSCs.…”

Section: Mechanisms Of Reprogramming In Humansmentioning

confidence: 99%

Mechanism of human somatic reprogramming to iPS cell

Teshigawara

Cho

Kameda

et al. 2017

Laboratory Investigation

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Somatic reprogramming to induced pluripotent stem cells (iPSC) was realized in the year 2006 in mice, and in 2007 in humans, by transiently forced expression of a combination of exogenous transcription factors. Human and mouse iPSCs are distinctly reprogrammed into a 'primed' and a 'naïve' state, respectively. In the last decade, puzzle pieces of somatic reprogramming have been collected with difficulty. Collectively, dissecting reprogramming events and identification of the hallmark of sequentially activated/silenced genes have revealed mouse somatic reprogramming in fragments, but there is a long way to go toward understanding the molecular mechanisms of human somatic reprogramming, even with developing technologies. Recently, an established human intermediately reprogrammed stem cell (iRSC) line, which has paused reprogramming at the endogenous OCT4-negative/exogenous transgene-positive pre-MET (mesenchymal-to-epithelial-transition) stage can resume reprogramming into endogenous OCT4-positive iPSCs only by change of culture conditions. Genome-editing-mediated visualization of endogenous OCT4 activity with GFP in living iRSCs demonstrates the timing of OCT4 activation and entry to MET in the reprogramming toward iPSCs. Applications of genome-editing technology to pluripotent stem cells will reshape our approaches for exploring molecular mechanisms.

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Metabolome Profiling of Partial and Fully Reprogrammed Induced Pluripotent Stem Cells

Cited by 28 publications

References 26 publications

Physiological oxygen culture reveals retention of metabolic memory in human induced pluripotent stem cells

Physiological oxygen culture reveals retention of metabolic memory in human induced pluripotent stem cells

Energy Metabolism Regulates Stem Cell Pluripotency

Mechanism of human somatic reprogramming to iPS cell

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