Zscan4 Dramatically Improves iPS Cell Quality
Source:
Time: 2012-11-19
Induced pluripotent stem cells (iPSCs) generated by “Yamanaka factors” hold great potential for use in autologous cell therapy. Recently, a team of researchers from Chinese Academy of Sciences and Nankai University demonstrate that Zscan4, a unique gene highly expressed at the zygotic genome activation stage, in combination with the Yamanaka factors, not only significantly promotes iPS cell generation but also dramatically improves the quality of iPSCs probably via rapid enhancement of telomere lengthening.
Recent reports show that genomic abnormalities exist in human iPSCs. Meanwhile, most mouse iPSCs are not fully pluripotent as evaluated by the tetraploid complementation assay (TCA), which is probably associated with DNA damage response (DDR) activated by “Yamanaka factors” during the reprogramming process. In contrast, nuclear transfer (NT) can faithfully reprogram somatic cells into embryonic stem cell (ntESCs); and these ntESCs can efficiently give rise to live-borne mice by TCA. These results lead to a hypothesis that factors involved in oocyte-induced reprogramming may stabilize the somatic genome during the reprogramming process, which may result in improved quality of the resulting iPS cells.
To test this hypothesis, JIANG Jing, LV Wenjian, YE Xiaoying and their colleagues, under the supervision of Dr. LI Jinsong from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences and Dr. LIU Lin from Nankai University, screened for candidate factors that could decrease DDR signals during iPSC induction. They found that Zscan4 not only remarkably reduces the DDR but also markedly promotes the efficiency of iPSC generation. Mechanistically, the inclusion of Zscan4 appears to stabilize the genomic DNA, and enhance telomere lengthening as early as 3 days post infection of exogenous genes by a telomere DNA recombination–based mechanism. As a result, iPSCs generated with the addition of Zscan4 exhibit longer telomeres compared with classical iPSCs. Strikingly, more than 50% of iPSC lines (11/19) produced via the “Zscan4 protocol” give rise to live-borne all-iPSC mice by TCA, compared to 1/12 for lines produced from classical Yamanaka factors. These results provide the first demonstration that maintaining the genomic stability during reprogramming promotes the generation of higher quality iPSCs.
This work entitled “Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation” was published in Cell Research as a Featured Article on Nov 13th, 2012.
This study was supported by grants from Chinese Academy of Sciences, Ministry of Science and Technology, National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality.
AUTHOR CONTACT:
LI Jinsong
Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
Phone:86-21-54921422; E-mail: jsli@sibs.ac.cn
LIU Lin
Nankai University, Tianjin, China
Zscan4 leads to longer telomeres (A and B) in the resultant iPS cells and significantly improves the developmental potential (C and D) of iPS cells. (Image provided by Dr. LI Jinsong)
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