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Published online 9 August 2009 | Nature | doi:10.1038/news.2009.809
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Immortality improves cell reprogramming
Knocking out genes with a role in cancer prevention helps produce stem cells.
Specialized adult cells made 'immortal' through the blockade of an antitumour pathway can be turned into stem-like cells quickly and efficiently.
The findings — which should make it easier to generate patient-specific cells from any tissue type, including certain diseased cells that have proved difficult to transform — suggest that cellular reprogramming and cancer formation are inextricably linked.
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very similar work was published in Cell Stem Cell last year by Deng group of Peking University, China. They used p53 siRNA. 1: Cell Stem Cell. 2008 Nov 6;3(5):475-9. Two supporting factors greatly improve the efficiency of human iPSC generation.Zhao Y, Yin X, Qin H, Zhu F, Liu H, Yang W, Zhang Q, Xiang C, Hou P, Song Z, Liu Y, Yong J, Zhang P, Cai J, Liu M, Li H, Li Y, Qu X, Cui K, Zhang W, Xiang T, Wu Y, Zhao Y, Liu C, Yu C, Yuan K, Lou J, Ding M, Deng H.
Thanks for you comment on the background to the paper. One of the first studies linking the p53 pathway to reprogramming was actually published five years ago by Kyoto University's Takashi Shinohara, who showed that mouse germ cells spontaneously formed embryonic-like stem cells when his team knocked out p53 (Cell 119, 1001-1012, 2004). Indeed, last year, Deng and his colleagues found that disabling p53 with RNA interference greatly increased human iPS cell numbers, but only in combination with a little-studied transcription factor called Utf1 as well as the standard reprogramming factors. This remained little more than a curious observation until the most recent suite of studies.
Dear Elie, congratulations for your piece, but there is one fact that you didn´t get right in your reply above. Deng and his colleagues demonstrated that a siRNA against p53 improves reprogramming both ALONE and in combination with Utf1.
These publications proved beyond any double Shi V. Liu's PUBLISHED conclusion (see http://im1.biz/iPS.htm) that iPSCs are incorrectly programmed stem cells or, in other words, man-made cancer stem cells (mmCSCs). If Nature allows, I intend to write the following Communications Arising: 1. Increasing iPSC reprogramming efficiency by eliminating tumor-suppressing pathway p53–p21 Communications Arising from CHyenjong Hong, Kazutoshi Takahashi, Tomoko Ichisaka, Takashi Aoi, Osami Kanagawa, Masato Nakagawa, Keisuke Okita & Shinya Yamanaka doi:10.1038/nature08235 2. p53 tumour suppressor pathway is indeed linked to iPS reprogramming Communications Arising from Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V. Wang, Sergio Menendez, Laura Batlle Morera, Angel Raya, Geoffrey M. Wahl & Juan Carlos Izpisúa Belmonte doi:10.1038/nature08311 3. Knocking down a central tumor-suppressing Ink4/Arf locus enhanced iPS cell reprogramming Communications Arising from Han Li, Manuel Collado, Aranzazu Villasante, Katerina Strati, Sagrario Ortega, Marta Cañamero, Maria A. Blasco & Manuel Serrano doi:10.1038/nature08290 4. Abrogating tumor-suppressing p53 ensured generation of iPSCs with persistent DNA damage and chromosomal aberrations Communications Arising from Rosa M. Marión, Katerina Strati, Han Li, Matilde Murga, Raquel Blanco, Sagrario Ortega, Oscar Fernandez-Capetillo, Manuel Serrano & Maria A. Blasco doi:10.1038/nature08287 5. Finally, iPSCs are recognized as immortalized cells, just as most cancer cells Communications Arising from Jochen Utikal, Jose M. Polo, Matthias Stadtfeld, Nimet Maherali, Warakorn Kulalert, Ryan M. Walsh, Adam Khalil, James G. Rheinwald & Konrad Hochedlinger doi:10.1038/nature08285 Please let me know if anyone wish to join me in writing these Communications Arising manuscripts.
Excerpt from Zhang et al.'s publication "Cancer Cell Formation by iPS Techniques: Mechanisms and Testing Approaches" (Logical Biology 9 (1):22-41, 2009)<<< ......following the Central Dogma, it will make no difference if the acceleration of cell reproduction is initiated at the gene, the RNA or the protein level. As long as the end result is a cell reproduction which is "uncontrolled" then it is a generation of neoplasm, benign tumor or malignant cancer./// For example, the transfection with oncogenes c-myc has recently been shown to enhance glutaminase expression (36) which can shift energy metabolism in mitochondria from catabolism to anabolism and thus meet the requirement of mass production – proliferation of more cells. When this "reprogramming" happens to some stem cells as it was done with G1 and G2 iPSCs, the uncontrolled proliferation of transformed stem cells can form cancers in recipients receiving the stem cell treatment./// For another example, oncoprotein c-Myc regulates microRNA (39) and thus influence cell proliferation and apoptosis (40). A recent study even showed that microRNA repression by Myc contributes to tumorigenesis through the binding of Myc to miRNA promoters (41). The direct consequence of this binding is unknown. But an energy mutation mitochondrion tumorigenesis (42) may well explain cancer formation starting from the introduction of c-Myc, as done in the "chemical engineering" approach for generating G3 iPSCs (25)./// Cell reproduction activation can also be achieved by eliminating or inactivating tumor-suppressing pathways. It is well known that mutations in tumor-suppressing genes can lead to tumor formation (43). A recent study even showed that mouse fibroblasts lacking retinoblastoma protein (RB) function form spheres and undergo reprogramming to a cancer stem cell phenotype (44). Ironically, this cancer cell formation, along with the generation of iPSCs, has been praised as "recreating stem cells: a novel entrance to the fountain of youth" (45). Thus, very likely some future iPSCs may be "induced" in this fashion. But the linkage of this repression of tumor-suppressors with cancer formation is well known (46). Future study should reveal if taking out cancer-suppressing "guards" (tumor-suppressing genes or their cytoplasm “messengers� may be linked with an abnormal metabolism in mitochondria in these (generation 4?) iPSCs./// Thus, replacing a low-mass-yield oxidative phosphorylation energy program in typical eukaryotic cells with a high-mass-yield aerobic glycolysis energy program similar to prokaryotic cells may be the Holy Grail for iPS reprogramming that resulted in "efficient" production of more "immortal" transformed and thus cancerous stem cells.