Enhancement of human embryonic stem cell pluripotency through inhibition of the mitochondrial respiratory chain

Varum, Sandra; Momčilović, Olga; Castro, Carlos; Ben‐Yehudah, Ahmi; Ramalho‐Santos, João; Navara, Christopher S.

doi:10.1016/j.scr.2009.07.002

Cited by 156 publications

(133 citation statements)

References 50 publications

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“…Hence, hESCs in their self-renewal state appear to rely more on anaerobic rather than aerobic mitochondrial respiration, in agreement with the hypoxic environment to which early-stage mammalian embryos are exposed [24] and the growth improvement displayed by hESCs under low oxygen tension [25][26][27]. Accordingly, inhibition of mitochondrial respiratory chain has been recently found associated with enhancement of hESC pluripotency [26].…”

Section: Introductionsupporting

confidence: 54%

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

et al. 2010

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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.

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Section: Introductionsupporting

confidence: 54%

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

et al. 2010

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“…Yet, present knowledge indicates that Warburg effect might not be the prime cause of cancer. Mitochondrial defects in normal cells lead invariably to HIF-1a stabilization: while succinate dehydrogenase and fumarate hydratase dysfunction leads to prolyl hydroxylase inactivation by their substrates that leak into the cytosol (King et al, 2006), ETC blockers enhance mitochondrial ROS production (Varum et al, 2009), which have the same effect. HIF-1 activity alone retards normal cell proliferation (Koshiji et al, 2004).…”

Section: Perspectivesmentioning

confidence: 99%

Metabolic reprogramming of the tumor

2012

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Cancer is classically considered as a genetic and, more recently, epigenetic multistep disease. Despite seminal studies in the 1920s by Warburg showing a characteristic metabolic pattern for tumors, cancer bioenergetics has often been relegated to the backwaters of cancer biology. This review aims to provide a historical account on cancer metabolism research, and to try to integrate and systematize the metabolic strategies in which cancer cells engage to overcome selective pressures during their inception and evolution. Implications of this renovated view on some common concepts and in therapeutics are also discussed.

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“…Thus, hypoxic environment and anaerobic metabolism appear to favorably support self-renewal and pluripotency. Accordingly, hypoxic culture and mitochondrial inhibition have been associated with reduced ES cell differentiation and more recently with improved generation of iPS cells (Ezashi et al, 2005;Varum et al, 2009;Yoshida et al, 2009). For these reasons, mitochondrial structure and function have been suggested as indicators of stem cell competence Lonergan et al, 2006;Siggins et al, 2008;Parker et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells

Prigione¹,

Adjaye²

2010

Int. J. Dev. Biol.

121

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Reprogramming somatic cells to induced pluripotent stem (iPS) cells transforms differentiated cells to an embryonic stem (ES)cell-like state characterized by the acquisition of pluripotency and self-renewal capabilities. We recently demonstrated that human ES and iPS cells share similar mitochondrial properties and bioenergetic metabolism, which are distinct from those of fibroblasts. In the present study, we have applied a global transcriptome profiling approach to compare the mitochondrial-related transcriptional signature upon the loss of self renewal and pluripotency in human ES and iPS cells. This was achieved by inducing in vitro and in vivo spontaneous differentiation. ES and iPS cells showed a similar degree of correlation both in the undifferentiated state and in all the stages of differentiation analyzed, suggesting that their transcriptional similarities are retained upon differentiation. Moreover, comparable induction of transcripts involved in epithelial to mesenchymal transition was observed in both cell types. Analysis of mitochondrial-related nuclear transcripts revealed consensual regulation of genes involved in mitochondrial biogenesis and bioenergetic metabolism upon in vitro differentiation of human ES and iPS cells, while specific differences were identified within in vivo differentiated cells. Significant changes were not detected for antioxidant-related genes. Finally, we formulate a "metabolic state hypothesis" linking mitochondrial state and cellular metabolism to the stage of differentiation. Overall, our data unveil differences and similarities between human ES and iPS cells during spontaneous differentiation and suggest that the study of mitochondrial and metabolic remodeling may reveal key mechanisms underlying the acquisition, maintenance and exit of a self-renewing pluripotent state.

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Enhancement of human embryonic stem cell pluripotency through inhibition of the mitochondrial respiratory chain

Cited by 156 publications

References 50 publications

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

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

Metabolic reprogramming of the tumor

Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells

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