山中伸弥《Nature》iPS又一创举

　　

生物通报道，iPS的创始人山中伸弥在iPS的研究上始终站在最前沿，最近其关于iPS的研究性文章Suppression of induced pluripotent stem cell generation by the p53–p21 pathway再度发表在Nature上。

 

最近iPS可谓频频登顶级杂志，仅Nature杂志而言，近两期就有8篇iPS的文章发表，其中较为轰动的是iPS全能性的证明文章，笔者估计，近期的Nature将出版iPS的专题，以便介绍近期iPS的热门进展。

 

iPS技术发展至今已经是百家争鸣的境地，各种改良的技术都时有出现。不过，转化效率低一直都是科学家头疼的问题。如果仅从研究来看，这也许并不致命，但是从临床来看，这一问题可能成为制约iPS临床转化的障碍之一。

 

鉴于c-Myc有致癌性，很多科学家都试图将这一基因取缔掉，以降低致癌性。但，遗憾的是，致癌性虽降低了，效率却更低了。

 

科学家于是尝试用siRNA阻断p53降低致癌性，以便保留c-Myc，结果成功了，效率比先前更高，可是无人知道个中原因和机制。

 

山中伸弥的这篇Nature文章就是解决这个问题。他们发现取消c-Myc基因后用siRNA阻断p53有助提高iPS转化效率，有趣的是，不用病毒载体诱导iPS，而用质粒诱导iPS时，阻断p53同样可提高iPS转化率。

 

用芯片分析发现，人和小鼠有34个涉及p53调节的基因，这些基因通过p21-p53通路调控iPS的致癌性和转化效率。

（生物通 小茜）

生物通推荐原文检索

Suppression of induced pluripotent stem cell generation by the p53–p21 pathway

Hyenjong Hong1,2, Kazutoshi Takahashi1, Tomoko Ichisaka1,3, Takashi Aoi1, Osami Kanagawa4, Masato Nakagawa1,2, Keisuke Okita1 & Shinya Yamanaka1,2,3,5

 

Center for iPS Cell Research and Application (CiRA), Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan

Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan

Yamanaka iPS Cell Special Project, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Laboratory for Autoimmune Regulation, RIKEN Center for Allergy and Immunology, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan

Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA

Correspondence to: Shinya Yamanaka1,2,3,5 Correspondence and requests for materials should be addressed to S.Y. (Email: [e-mail]).

 

 

【Abstract】

Induced pluripotent stem (iPS) cells can be generated from somatic cells by the introduction of Oct3/4 (also known as Pou5f1), Sox2, Klf4 and c-Myc, in mouse1, 2, 3, 4 and in human5, 6, 7, 8. The efficiency of this process, however, is low9. Pluripotency can be induced without c-Myc, but with even lower efficiency10, 11. A p53 (also known as TP53 in humans and Trp53 in mice) short-interfering RNA (siRNA) was recently shown to promote human iPS cell generation12, but the specificity and mechanisms remain to be determined. Here we report that up to 10% of transduced mouse embryonic fibroblasts lacking p53 became iPS cells, even without the Myc retrovirus. The p53 deletion also promoted the induction of integration-free mouse iPS cells with plasmid transfection. Furthermore, in the p53-null background, iPS cells were generated from terminally differentiated T lymphocytes. The suppression of p53 also increased the efficiency of human iPS cell generation. DNA microarray analyses identified 34 p53-regulated genes that are common in mouse and human fibroblasts. Functional analyses of these genes demonstrate that the p53–p21 pathway serves as a barrier not only in tumorigenicity, but also in iPS cell generation.