The Expression of Mitochondrial DNA Transcription Factors during Early Cardiomyocyte<i>In Vitro</i>Differentiation from Human Embryonic Stem Cells

John, Justin C. St.; Ramalho‐Santos, João; Gray, Heather; Petrosko, Patti; Rawe, Vanesa Y.; Navara, Christopher S.; Simerly, Calvin; Schatten, Gerald

doi:10.1089/clo.2005.7.141

Cited by 216 publications

(168 citation statements)

References 41 publications

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“…Studies of organelle number and functionality confirmed a low content of mitochondrial DNA (mtDNA) and low levels of intracellular ATP and ROS [7,8,23]. 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].…”

Section: Introductionmentioning

confidence: 82%

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: Introductionmentioning

confidence: 82%

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

et al. 2010

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“…27 For example, increased Dcm was evident during differentiation of ESCs into cardiomyocytes. 19 In contrast, other reports describe elevated Dcm in undifferentiated ESCs 30 and in induced pluripotent SCs, decreasing after differentiation. 31 We found that P19SCs present low Dcm, showing small differences when treated with FCCP.…”

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confidence: 89%

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

et al. 2014

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The relationship between mitochondrial metabolism and cell viability and differentiation in stem cells (SCs) remains poorly understood. In the present study, we compared mitochondrial physiology and metabolism between P19SCs before/after differentiation and present a unique fingerprint of the association between mitochondrial activity, cell differentiation and stemness. In comparison with their differentiated counterparts, pluripotency of P19SCs was correlated with a strong glycolytic profile and decreased mitochondrial biogenesis and complexity: round, low-polarized and inactive mitochondria with a closed permeability transition pore. This decreased mitochondrial capacity increased their resistance against dichloroacetate. Thus, stimulation of mitochondrial function by growing P19SCs in glutamine/pyruvate-containing medium reduced their glycolytic phenotype, induced loss of pluripotent potential, compromised differentiation and became P19SCs sensitive to dichloroacetate. Because of the central role of this type of SCs in teratocarcinoma development, our findings highlight the importance of mitochondrial metabolism in stemness, proliferation, differentiation and chemoresistance. In addition, the present work suggests the regulation of mitochondrial metabolism as a tool for inducing cell differentiation in stem line therapies. Embryonal carcinoma cells, including the P19 cell line, are pluripotent cancer stem cells (CSCs) derived from pluripotent germ cell tumors called teratocarcinomas. These have been described as the malignant counterparts of embryonic stem cells (ESCs) and are considered a good model to study stem cell (SC) differentiation. The P19 cell line can be maintained as undifferentiated cells (P19SCs) or differentiated (P19dCs) to any cell type of the three germ layers. Similar to ESCs, P19 cells differentiate with retinoic acid (RA) in a dose-dependent manner and depending on growth conditions. 1 Although differentiation generally yields a mixed population of differentiated cells, P19 cells grown in monolayer and treated with 1 mM RA primarily differentiate in endoderm or mesoderm, while retaining their immortality. 2,3Although some therapeutic approaches for regenerative medicine and to targeting CSCs are based on differentiation 4 and mitochondrial-targeted therapies, 5,6 very little is known about the role of mitochondrial metabolism in SC maintenance and differentiation.7 Several mitochondrial characteristics that distinguish transformed cells from healthy cells have been described, 8 including increased mitochondrial transmembrane electric potential (Dcm), which may result from decreased mitochondrial ATP production under normoxia. Similarly, normal SCs primarily rely on glycolysis for energy supply, although the exact mechanism how this occurs in the presence of oxygen and the relationship between SC metabolism and cell fate control is not yet completely understood. 10Given the mitochondrial involvement in stemness and differentiation, 11 one can ask whether manipulation of mitochondrial physi...

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“…1). Consistently, mitochondria are less complex and fewer in number in human ESCs than in their differentiated progeny (Cho et al, 2006;Facucho-Oliveira et al, 2007;St John et al, 2005;Varum et al, 2011;Zhang et al, 2011b). Furthermore, studies analyzing mitochondrial respiration, glycolytic flux or proteomic profiles of purified adult HSCs have shown that these adult stem cells rely primarily on glycolysis to generate ATP (Miharada et al, 2011;Simsek et al, 2010;Unwin et al, 2006).…”

Section: Metabolic Properties Of Stem Cellsmentioning

confidence: 99%

Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate

Rafalski

Mancini

Brunet

2012

Journal of Cell Science

155

120

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SummaryMetabolism is influenced by age, food intake, and conditions such as diabetes and obesity. How do physiological or pathological metabolic changes influence stem cells, which are crucial for tissue homeostasis? This Commentary reviews recent evidence that stem cells have different metabolic demands than differentiated cells, and that the molecular mechanisms that control stem cell self-renewal and differentiation are functionally connected to the metabolic state of the cell and the surrounding stem cell niche. Furthermore, we present how energy-sensing signaling molecules and metabolism regulators are implicated in the regulation of stem cell self-renewal and differentiation. Finally, we discuss the emerging literature on the metabolism of induced pluripotent stem cells and how manipulating metabolic pathways might aid cellular reprogramming. Determining how energy metabolism regulates stem cell fate should shed light on the decline in tissue regeneration that occurs during aging and facilitate the development of therapies for degenerative or metabolic diseases.

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The Expression of Mitochondrial DNA Transcription Factors during Early CardiomyocyteIn VitroDifferentiation from Human Embryonic Stem Cells

Cited by 216 publications

References 41 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

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate

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