期刊
NATURE CELL BIOLOGY
卷 19, 期 9, 页码 1037-+出版社
NATURE PORTFOLIO
DOI: 10.1038/ncb3598
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资金
- NIH [R00HL093212, R01AG043531, CA196631-01A1, R21HD081682, R24DK092760, P01CA087497, R01GM112722]
- TriStemStar Foundation [2013-049]
- Louis V Gerstner, Jr. Young Investigators awards
- Geoffrey Beene Junior Chair Award
- Sidney Kimmel Scholar Award
- Alfred W. Bressler Scholars Endowment Fund
- MSKCC Society Fund
- NIH Cancer Center [P30 CA008748]
- UAB Development Fund
- Mayo Clinic Center for Individualized Medicine
- HHMI
- medical faculty of Heinrich Heine University, Dusseldorf
- MSKCC Single Cell Sequencing Initiative
- William and Joyce O'Neil Research Fund
- STARR visiting fellows programme
- American Italian Cancer Foundation
- Women in Science Rockefeller fellowship
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.
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