Document Detail


Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation.
MedLine Citation:
PMID:  23147797     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Induced pluripotent stem (iPS) cells generated using Yamanaka factors have great potential for use in autologous cell therapy. However, genomic abnormalities exist in human iPS cells, and most mouse iPS cells are not fully pluripotent, as evaluated by the tetraploid complementation assay (TCA); this is most likely associated with the DNA damage response (DDR) occurred in early reprogramming induced by Yamanaka factors. In contrast, nuclear transfer can faithfully reprogram somatic cells into embryonic stem (ES) cells that satisfy the TCA. We thus hypothesized that factors involved in oocyte-induced reprogramming may stabilize the somatic genome during reprogramming, and improve the quality of the resultant iPS cells. To test this hypothesis, we screened for factors that could decrease DDR signals during iPS cell induction. We determined that Zscan4, in combination with the Yamanaka factors, not only remarkably reduced the DDR but also markedly promoted the efficiency of iPS cell generation. The inclusion of Zscan4 stabilized the genomic DNA, resulting in p53 downregulation. Furthermore, Zscan4 also enhanced telomere lengthening as early as 3 days post-infection through a telomere recombination-based mechanism. As a result, iPS cells generated with addition of Zscan4 exhibited longer telomeres than classical iPS cells. Strikingly, more than 50% of iPS cell lines (11/19) produced via this "Zscan4 protocol" gave rise to live-borne all-iPS cell mice as determined by TCA, compared to 1/12 for lines produced using the classical Yamanaka factors. Our findings provide the first demonstration that maintaining genomic stability during reprogramming promotes the generation of high quality iPS cells.
Authors:
Jing Jiang; Wenjian Lv; Xiaoying Ye; Lingbo Wang; Man Zhang; Hui Yang; Maja Okuka; Chikai Zhou; Xuan Zhang; Lin Liu; Jinsong Li
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-13
Journal Detail:
Title:  Cell research     Volume:  23     ISSN:  1748-7838     ISO Abbreviation:  Cell Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-06-18     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  9425763     Medline TA:  Cell Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  92-106     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
DNA Repair
Genomic Instability*
Humans
Induced Pluripotent Stem Cells / cytology*
Mice
Nuclear Reprogramming
Telomere / metabolism
Teratoma / pathology
Tetraploidy
Transcription Factors / genetics,  metabolism*
Transfection
Tumor Suppressor Protein p53 / metabolism
Chemical
Reg. No./Substance:
0/Transcription Factors; 0/Tumor Suppressor Protein p53; 0/Zscan4f protein, mouse
Comments/Corrections

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