Abstract
Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS-glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients' own cells that are safe for transplantation.
MeSH terms
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Adult Stem Cells / metabolism*
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Adult Stem Cells / pathology
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Age Factors
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Aged
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Aging / genetics
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Aging / metabolism*
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Aging / pathology
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Animals
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Animals, Newborn
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Apoptosis
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Cell Differentiation
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Cell Proliferation
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Cells, Cultured
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Cellular Reprogramming Techniques
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Cellular Reprogramming*
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DNA Damage
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Embryonic Stem Cells / metabolism*
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Embryonic Stem Cells / pathology
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Gene Expression Regulation, Developmental
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Genomic Instability*
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Gestational Age
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Glutathione / metabolism
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Humans
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Induced Pluripotent Stem Cells / metabolism*
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Induced Pluripotent Stem Cells / pathology
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, Transgenic
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Oxidative Stress
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Phenotype
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Reactive Oxygen Species / metabolism
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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Signal Transduction
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Tissue Donors*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
Substances
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DNA-Binding Proteins
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KLF4 protein, human
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Klf4 protein, mouse
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Kruppel-Like Factor 4
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Kruppel-Like Transcription Factors
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MYC protein, human
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Octamer Transcription Factor-3
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POU5F1 protein, human
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Proto-Oncogene Proteins c-myc
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Reactive Oxygen Species
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SOX2 protein, human
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SOXB1 Transcription Factors
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Transcription Factors
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ZFP206 protein, mouse
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ZSCAN10 protein, human
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Glutathione