体细胞重编程技术具有重要的理论和实践意义。在再生医学研究中，通过该技术获得来自患者的多能干细胞，进一步用于自体移植可以避免免疫排斥问题，从而使其成为干细胞和再生医学研究的热点领域。
核移植和iPS技术均能将体细胞重编为多能干细胞，然而两者的重编程的能力却不同。核移植后获得的胚胎干细胞（ESCs）具有与正常ESCs相似的多能性，通过四倍体囊胚注射能够获得小鼠，然而大部分的iPS细胞却没有这一能力。最近的研究发现，人的iPS细胞存在不少的遗传变异。由此，可以推测参与核移植诱导体细胞重编程的因子可能对遗传物质的稳定起着重要的作用，如果将这些因子应用到iPS技术中，可能会维持重编程过程中细胞遗传物质的稳定性，从而改善iPS细胞的质量。
11月13日，国际学术期刊Cell Research在线发表了中科院上海生科院生化与细胞所李劲松研究组与南开大学刘林研究组的最新研究成果，他们发现将核移植过程中的重要因子Zscan4与Yamanaka因子共同使用，不仅能够显著提高iPS细胞的产生效率，而且降低IPS细胞形成过程中DNA的损伤，显著地改善了iPS细胞的质量。
为了获得对重编程细胞的遗传物质能起保护作用的重要因子，李劲松研究组的蒋婧和吕纹简等同学建立了一个筛选系统，他们发现其中Zscan4能显著提高iPS细胞的形成效率。进一步研究发现Zscan4能够促进重编程过程中细胞端粒区以及非端粒区遗传物质的稳定。深入研究发现，Zscan4能够快速延长重编程细胞的端粒，重编程后第三天，Zscan4组的细胞端粒比没有Zscan4组的长约5KB；这种快速的端粒延长是通过姐妹染色体互换完成，而不是通过传统的端粒酶介导。由于Zscan4的介入稳定了重编程细胞的基因组，研究人员发现iPS细胞的质量得到了显著地改善，19株中有11株(58%)通过四倍体囊胚注射能够获得完成来自iPS细胞的小鼠，而通过传统Yamanaka方法获得的iPS细胞，11株中只有1株能够获得完全iPS细胞的小鼠。这些结果提示，在细胞重编程过程，除了多能性的建立，细胞遗传物质稳定性的维持也非常重要。这一结果对通过Yamanaka方法获得iPS细胞研究注入了新的思路，为获得更安全iPS细胞应用于再生医学提供了重要的理论依据。
该项工作得到了国家科技部、国家基金委、中国科学院战略性先导科技专项以及上海市科委经费的支持。（生物谷Bioon.com）
doi: 10.1038/cr.2012.157
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Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation.
Jiang J, Lv W, Ye X, Wang L, Zhang M, Yang H, Okuka M, Zhou C, Zhang X, Liu L, Li J.
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
