ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors

Maria Skamagki; Cristina Correia; Percy Yeung; Timour Baslan; Samuel Beck; Cheng Zhang; Christian A Ross; Lam Dang; Zhong Liu; Simona Giunta; Tzu-Pei Chang; Joye Wang; Aparna Ananthanarayanan; Martina Bohndorf; Benedikt Bosbach; James Adjaye; Hironori Funabiki; Jonghwan Kim; Scott Lowe; James J Collins; Chi-Wei Lu; Hu Li; Rui Zhao; Kitai Kim

doi:10.1038/ncb3598

ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors

Nat Cell Biol. 2017 Sep;19(9):1037-1048. doi: 10.1038/ncb3598. Epub 2017 Aug 28.

Authors

Maria Skamagki¹, Cristina Correia², Percy Yeung³, Timour Baslan⁴, Samuel Beck⁵, Cheng Zhang², Christian A Ross², Lam Dang¹, Zhong Liu⁶, Simona Giunta⁷, Tzu-Pei Chang¹, Joye Wang¹, Aparna Ananthanarayanan¹, Martina Bohndorf⁸, Benedikt Bosbach⁴, James Adjaye⁸, Hironori Funabiki⁷, Jonghwan Kim⁵, Scott Lowe⁴, James J Collins⁹, Chi-Wei Lu³, Hu Li², Rui Zhao⁶, Kitai Kim¹

Affiliations

¹ Cancer Biology and Genetics Program, Center for Cell Engineering, Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute for Cancer Research, and Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10065, USA.
² Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55904, USA.
³ Department of Obstetrics, Gynecology and Reproductive Sciences, Child Health Institute of New Jersey, New Brunswick, New Jersey 08901, USA.
⁴ Howard Hughes Medical Institute, Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute for Cancer Research, and Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.
⁵ Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.
⁶ Department of Biochemistry and Molecular Genetics, Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
⁷ Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, New York 10065, USA.
⁸ Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University, Düsseldorf D-40225, Germany.
⁹ Department of Biological Engineering, Massachusetts Institute of Technology, Broad Institute of MIT and Harvard, and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02118, USA.

PMID: 28846095
PMCID: PMC5843481
DOI: 10.1038/ncb3598

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

Adult Stem Cells / metabolism*
Adult Stem Cells / pathology
Age Factors
Aged
Aging / genetics
Aging / metabolism*
Aging / pathology
Animals
Animals, Newborn
Apoptosis
Cell Differentiation
Cell Proliferation
Cells, Cultured
Cellular Reprogramming Techniques
Cellular Reprogramming*
DNA Damage
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Embryonic Stem Cells / metabolism*
Embryonic Stem Cells / pathology
Gene Expression Regulation, Developmental
Genomic Instability*
Gestational Age
Glutathione / metabolism
Humans
Induced Pluripotent Stem Cells / metabolism*
Induced Pluripotent Stem Cells / pathology
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism
Mice
Mice, Transgenic
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Oxidative Stress
Phenotype
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Reactive Oxygen Species / metabolism
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism
Signal Transduction
Tissue Donors*
Transcription Factors / genetics
Transcription Factors / metabolism*
Transfection

Substances

DNA-Binding Proteins
KLF4 protein, human
Klf4 protein, mouse
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
MYC protein, human
Octamer Transcription Factor-3
POU5F1 protein, human
Proto-Oncogene Proteins c-myc
Reactive Oxygen Species
SOX2 protein, human
SOXB1 Transcription Factors
Transcription Factors
ZFP206 protein, mouse
ZSCAN10 protein, human
Glutathione

Abstract

MeSH terms

Substances

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