Energy Metabolism in Human Pluripotent Stem Cells and Their Differentiated Counterparts

Abstract

BackgroundHuman 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 FindingsWe 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/FindingsOur 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).

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

“…Analysis of chromatin status at the single-cell level, although technically challenging, will ultimately reveal the epigenetic mechanisms of the reprogramming. Several recent studies revealed that ESCs have a specialized metabolic profile [176][177][178][179][180]. Interestingly, chromatin modification has also been associated with metabolism in the case of cancer cells [191].…”

“…The metabolic profile of differentiated cells, which favors oxidative phosphorylation, is reset to a glycolysis-dependent ESC-like state after reprogramming [176][177][178][179][180]. This metabolic resetting takes place before pluripotency is established [179].…”

AMP-activated Protein Kinase Stimulates Warburg-like Glycolysis and Activation of Satellite Cells during Muscle Regeneration

“…Recent studies suggest the importance of metabolic transition in regulating the quiescence, activation, proliferation, and differentiation of stem cells (14,15,37). OXPHOS and glycolysis are two major metabolic pathways generating energy in mammalian cells (38).…”

iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

“…In contrast, stem cells mainly rely on anaerobic glycolysis followed by lactic acid fermentation in the cytosol to produce energy and thus fewer reactive oxygen species are generated [74] . Consequently, the reprogramming of somatic cells that utilize mitochondrial oxidation to iPSCs would require a switch in metabolism.…”