The Senescence-Related Mitochondrial/Oxidative Stress Pathway is Repressed in Human Induced Pluripotent Stem Cells

Abstract

The ability of stem cells to propagate indefinitely is believed to occur via the fine modulation of pathways commonly involved in cellular senescence, including the telomerase, the p53, and the mitochondrial/oxidative stress pathways. Induced pluripotent stem cells (iPSCs) are a novel stem cell population obtained from somatic cells through forced expression of a set of genes normally expressed in embryonic stem cells (ESCs). These reprogrammed cells acquire self-renewal properties and appear almost undistinguishable from ESCs in terms of morphology, gene expression, and differentiation potential. Accordingly, iPSCs exhibit alterations of the senescence-related telomerase and p53 signaling pathways. However, although treatments with antioxidants have been recently shown to enhance cellular reprogramming, detailed information regarding the state of the mitochondrial/oxidative stress pathway in iPSCs is still lacking. Mitochondria undergo specific changes during organismal development and aging. Thus, addressing whether somatic mitochondria within iPSCs acquire ESC-like features or retain the phenotype of the parental cell is an unanswered but relevant question. Herein, we demonstrate that somatic mitochondria within human iPSCs revert to an immature ESC-like state with respect to organelle morphology and distribution, expression of nuclear factors involved in mitochondrial biogenesis, content of mitochondrial DNA, intracellular ATP level, oxidative damage, and lactate generation. Upon differentiation, mitochondria within iPSCs and ESCs exhibited analogous maturation and anaerobic-to-aerobic metabolic modifications. Overall, the data highlight that human iPSCs and ESCs, although not identical, share similar mitochondrial properties and suggest that cellular reprogramming can modulate the mitochondrial/oxidative stress pathway, thus inducing a rejuvenated state capable of escaping cellular senescence.

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].…”

A Glycolytic Solution for Pluripotent Stem Cells

“…Consequently, a dramatic glycolytic shift occurs during cell fate conversion (from somatic cells to PSCs or from PSCs to differentiated progenies (Prigione et al, 2010). Two new papers in Cell Stem Cell and Cell Reports (Gu et al, 2016;Zhang et al, 2016) employ metabolic flux analysis to demonstrate that PSCs, even while maintaining pluripotency, dynamically modulate their glycolytic metabolism in response to changes in the culture conditions or conversion between different PSC states.…”

Reprogramming and Carcinogenesis—Parallels and Distinctions

“…Interestingly, iPS cells not only express stem cell markers, but also stem cell characteristics including anaerobic metabolism, low reactive oxygen species generation and decrease in mitochondrial mass and number (Armstrong et al, 2010;Prigione et al, 2010;Suhr et al, 2010). It has been suggested that the decrease in mitochondrial numbers contributes to lower generation of superoxide ions in iPS cells as compared to their progenitors (Vessoni et al, 2012).…”