Energy Metabolism in Human Pluripotent Stem Cells and Their Differentiated Counterparts

By Sandra Varum, A. S. Rodrigues, M. B. Moura, Olga Momčilović, Charles A. Easley, J. Ramalho‐Santos, B. Van Houten, G. Schatten. PLoS ONE, 2011

684 citations recorded by the source corpus.

Background Human pluripotent stem cells have the ability to generate all cell types present in the adult organism, therefore harboring great potential for the in vitro study of differentiation and for the development of cell-based therapies. Nonetheless their use may prove challenging as incomplete differentiation of these cells might lead to tumoregenicity. Interestingly, many cancer types have been reported to display metabolic modifications with features that might be similar to stem cells. Understanding the metabolic properties of human pluripotent stem cells when compared to their differentiated counterparts can thus be of crucial importance. Furthermore recent data has stressed distinct features of different human pluripotent cells lines, namely when comparing embryo-derived human embryonic stem cells (hESCs) and induced pluripotent stem cells (IPSCs) reprogrammed from somatic cells. Methodology/Principal Findings We compared the energy metabolism of hESCs, IPSCs, and their somatic counterparts. Focusing on mitochondria, we tracked organelle localization and morphology. Furthermore we performed gene expression analysis of several pathways related to the glucose metabolism, including glycolysis, the pentose phosphate pathway and the tricarboxylic acid (TCA) cycle. In addition we determined oxygen consumption rates (OCR) using a metabolic extracellular flux analyzer, as well as total intracellular ATP levels by high performance liquid chromatography (HPLC). Finally we explored the expression of key proteins involved in the regulation of glucose metabolism. Conclusions/Findings Our results demonstrate that, although the metabolic signature of IPSCs is not identical to that of hESCs, nonetheless they cluster with hESCs rather than with their somatic counterparts. ATP levels, lactate production and OCR revealed that human pluripotent cells rely mostly on glycolysis to meet their energy demands. Furthermore, our work points to some of the strategies which human pluripotent stem cells may use to maintain high glycolytic rates, such as high levels of hexokinase II and inactive pyruvate dehydrogenase (PDH).

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/83afcb05a7b5bd1264c15038e5e8193f062fcad9

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Citations in the corpus

Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. (2015, background): “In contrast, our results, tracking the first steps of differentiation, show a similar loss of glycolysis, minor difference in UCP2 expression, and an actual increase in PDHB (Figures 2E–2H), suggesting that a different mechanism might be responsible for the lack of oxidative phosphorylation in pluri”
Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination (2016, background): “Compared with differentiated cells, which utilise oxidative phosphorylation as the primary metabolic pathway, these PSCs possess largely underdeveloped and immature mitochondria that are few in number, thus maintaining high rates of glycolysis even under aerobic culture conditions, although a recent”
Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. (2016, neutral): “Stem cells seem to be in a metabolic state that is different from their progeny (Folmes et al., 2011; Varum et al., 2011).”
BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells (2013, methodology): “Metabolic Assays O2 consumption and lactate generation were measured using the Seahorse XF24 extracellular flux analyzer as previously described (Varum et al., 2011).”
The return of metabolism: biochemistry and physiology of the pentose phosphate pathway (2014, background): “…transcription factor p53 represents a tumour suppressor with well-established functions on genomic integrity, apoptosis and cell cycle control (Vazquez et al., 2008). p53 is the most commonly mutated gene in human cancers and its loss constitutes a pivotal mechanism of therapy failure…”
Metabolic Plasticity in Stem Cell Homeostasis and Differentiation (2012, neutral): “Genuine iPSCs demonstrate targeted upregulation of glycolytic enzymes and selective downregulation of electron transport chain subunits, associated with regression in mitochondrial density, distribution, and ultrastructure (Folmes et al., 2011a; Prigione et al., 2010; Varum et al., 2011).”