Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells

Cho, Young Min; Kwon, Sun Il; Pak, Youngmi Kim; Seol, Hye Won; Choi, Young Min; Park, Do Joon; Park, Kyong Soo; Lee, Hong Kyu

doi:10.1016/j.bbrc.2006.08.020

Cited by 434 publications

(414 citation statements)

References 19 publications

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“…Under in vivo condition, ESCs are exposed to a hypoxic environment of the uterine cavity. At this stage, ESCs have only a few mitochondria for ATP production [ 14 ]. It has been recently shown that during ESC differentiation, the number of mitochondria increases.…”

Section: Cell Viability Proliferation and Cell Cycle Analysismentioning

confidence: 99%

Effects of Oxidative Stress on Mouse Embryonic Stem Cell Proliferation, Apoptosis, Senescence, and Self-Renewal

Guo

Chakraborty

Rajan

et al. 2010

Stem Cells and Development

124

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Oxidative stress, associated with either normal metabolism or disease conditions, affects many cellular activities. Most of our knowledge in this fi eld is derived from fully differentiated cells. Embryonic stem cells (ESCs) have attracted enormous attention for their potential applications in cell therapy, but little is known about how the unique properties of ESCs are affected by oxidative stress. We have investigated the effects of oxidative stress induced by H 2 O 2 on several cellular activities of mouse ESCs. Like differentiated cells, ESCs are sensitive to H 2 O 2 -induced apoptosis when continuously exposed to H 2 O 2 at the concentrations above 150 μM. However, unlike differentiated cells, ESCs are resistant to oxidative stress induced senescence. This is demonstrated by the results that when subjected to a short-term sublethal concentration and duration of H 2 O 2 treatment, fi broblasts enter the senescent state with enlarged fl attened cell morphology concurrent with increased expression of senescence marker p21. On the contrary, ESCs neither show any sign of senescence nor express p21. Instead, ESCs enter a transient cell cycle arrest state, but they have remarkable recovery capacity to resume the normal cell proliferation rate without losing the ability of self-renewal and pluripotency. Our results further revealed that H 2 O 2 inhibits cell adhesion and the expression of cyclin D1, which are early events proceeding apoptosis and cell cycle arrest. In conclusion, our data suggest that ESCs are sensitive to H 2 O 2 toxicity, but may have unique mechanisms that prevent H 2 O 2 -induced senescence and protect self-renewal capacity.

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Section: Cell Viability Proliferation and Cell Cycle Analysismentioning

confidence: 99%

Effects of Oxidative Stress on Mouse Embryonic Stem Cell Proliferation, Apoptosis, Senescence, and Self-Renewal

Guo

Chakraborty

Rajan

et al. 2010

Stem Cells and Development

124

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show abstract

“…Genetic evaluation of therapeutic hESC E. Stephenson et al damage caused by reactive oxygen species and free radicals, which are generated during normal oxidative cell metabolism. Indeed, undifferentiated hESCs have a much lower expression of Cu/Zn-superoxide dismutase, glutathione peroxidase 1, and peroxiredoxin 1 and 2, which are enzymes that normally protect cells against such damage (Cho et al 2006 (Draper et al 2004;Hoffman & Carpenter 2005;Mitalipova et al 2005). Comparison of mechanical cutting of colonies and the use of enzymes for passage in the same hESC line suggested that mechanical cutting better supports maintenance of a normal karyotype in long-term culture; the enzyme-treated cell line was more likely to develop karyotype abnormalities (most often chromosome 12 and 17 trisomy).…”

Section: Extrinsic Factorsmentioning

confidence: 99%

Safety paradigm: genetic evaluation of therapeutic grade human embryonic stem cells

Stephenson

Ogilvie

Patel

et al. 2010

J. R. Soc. Interface.

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The use of stem cells for regenerative medicine has captured the imagination of the public, with media attention contributing to rising expectations of clinical benefits. Human embryonic stem cells (hESCs) are the best model for capital investment in stem cell therapy and there is a clear need for their robust genetic characterization before scaling-up cell expansion for that purpose. We have to be certain that the genome of the starting material is stable and normal, but the limited resolution of conventional karyotyping is unable to give us such assurance. Advanced molecular cytogenetic technologies such as array comparative genomic hybridization for identifying chromosomal imbalances, and single nucleotide polymorphism analysis for identifying ethnic background and loss of heterozygosity should be introduced as obligatory diagnostic tests for each newly derived hESC line before it is deposited in national stem cell banks. If this new quality standard becomes a requirement, as we are proposing here, it would facilitate and accelerate the banking process, since end-users would be able to select the most appropriate line for their particular application, thus improving efficiency and streamlining the route to manufacturing therapeutics. The pharmaceutical industry, which may use hESC-derived cells for drug screening, should not ignore their genomic profile as this may risk misinterpretation of results and significant waste of resources.

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“…32 Undifferentiated ESCs, iPSCs, and BMSCs were reported to display lower levels of mitochondrial mass and preferentially used nonoxidative glycolysis as a major source of energy. [35][36][37] The preferential use of nonoxidative glycolysis to cover the bioenergetic needs of undifferentiated stem cells might therefore explain the similar mitochondrial activity and metabolic rate of hTDSCs as measured using the alamarBlue assay at 2% and 20% O 2 tension despite the significantly grater cell number and DNA incorporation at 2% O 2 tension.…”

mentioning

confidence: 94%

Hypoxia-Mediated Efficient Expansion of Human Tendon–Derived Stem CellsIn Vitro

Lee

Lui

Rui

2012

Tissue Engineering Part A

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Tendons regenerate and repair slowly and inefficiently after injury. Tendon-derived stem cells (TDSCs) have been isolated recently and have been shown to promote tendon repair. The ability to achieve sufficient numbers of cells for transplantation is essential for their clinical application. In this study, we aimed to study the effect of low oxygen (O 2 ) tension (2%) on the clonogenicity, metabolic rate, DNA incorporation, population doubling time, b-galactosidase activity, immunophenotypes, multilineage differentiation potential, and tenocyte-like properties of human TDSCs (hTDSCs). hTDSCs were isolated from patellar tendon and characterized according to their adherence to plastic; colony-forming ability; multilineage differentiation potential; and high expression level of CD44, CD73, CD 90, and CD105 but low CD34, CD45, CD146, and Stro-1 at 20% O 2 tension. Low O 2 tension increased DNA incorporation but not metabolic rate of hTDSCs. It increased cell number 25% and the number of colonies but reduced the osteogenic, adipogenic, and chondrogenic differentiation potential of hTDSCs. The reduction in differentiation potential was associated with lower messenger RNA (mRNA) expression ratios of some lineage-related markers, including BGLAP, ALP, C/EBPa, PPARc2, ACAN, and SOX9; the expression of a tendon-related marker, TNMD, was greater. There was no significant difference in the production of collagenous to noncollagenous protein ratio; the immunophenotypes and b-galactosidase activity were similar at 2% and 20% O 2 tension. Hypoxia-preconditioned hTDSCs could successfully differentiate at 20% O 2 tension, as shown by the return of the mRNA expression ratios of lineage-related markers to levels comparable to cells pre-incubated and differentiated at 20% O 2 tension. In conclusion, hypoxia is advantageous for efficient expansion of hTDSCs in vitro for tendon tissue engineering.

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Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells

Cited by 434 publications

References 19 publications

Effects of Oxidative Stress on Mouse Embryonic Stem Cell Proliferation, Apoptosis, Senescence, and Self-Renewal

Effects of Oxidative Stress on Mouse Embryonic Stem Cell Proliferation, Apoptosis, Senescence, and Self-Renewal

Safety paradigm: genetic evaluation of therapeutic grade human embryonic stem cells

Hypoxia-Mediated Efficient Expansion of Human Tendon–Derived Stem CellsIn Vitro

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