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. CollinsChi Wei Lu, Hu Li, Rui Zhao, Kitai Kim

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1037-1048
Number of pages12
JournalNature Cell Biology
Volume19
Issue number9
DOIs
StatePublished - Sep 1 2017

ASJC Scopus subject areas

  • Cell Biology

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    Skamagki, M., Correia, C., Yeung, P., Baslan, T., Beck, S., Zhang, C., Ross, C. A., Dang, L., Liu, Z., Giunta, S., Chang, T. P., Wang, J., Ananthanarayanan, A., Bohndorf, M., Bosbach, B., Adjaye, J., Funabiki, H., Kim, J., Lowe, S., ... Kim, K. (2017). ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors. Nature Cell Biology, 19(9), 1037-1048. https://doi.org/10.1038/ncb3598