Adult mice generated from induced pluripotent stem cells

• Published in: Nature (London) Vol. 461; no. 7260; pp. 91 - 94
• Main Authors: Boland, Michael J., Hazen, Jennifer L., Nazor, Kristopher L., Rodriguez, Alberto R., Gifford, Wesley, Martin, Greg, Kupriyanov, Sergey, Baldwin, Kristin K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.09.2009; Nature Publishing Group
• Subjects: Aging; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal development; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Cell Dedifferentiation; Cell Differentiation; Cell Line; Cell Lineage; DNA binding proteins; Embryo, Mammalian - cytology; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryology: invertebrates and vertebrates. Teratology; Female; Fibroblasts - cytology; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic aspects; Humanities and Social Sciences; letter; Male; Medical sciences; Methods; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular embryology; multidisciplinary; Physiological aspects; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - physiology; Pregnancy; Properties; Proteins; Reproductive Techniques; Rodents; Science; Stem cells; Survival Rate; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; United States; Vertebrata; Mammalia; Cell line; Cell therapy; Mouse; Embryonic cell; Pluripotent cell; Stem cell; Rodentia; Medical application; Induced pluripotent stem
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature08310

Mice from iPS cells Since iPS (induced pluripotent stem) cells arrived on the scene in 2006, their properties have been measured against the yardstick of the true embryonic stem cells that they mimic. A clutch of recent papers, two of them published in this issue, reports the production of viable adult mice from iPS cells, a notable technical feat that shows that these cells are very close indeed to embryonic cells in their potential to produce cells for all tissues and all organs. Zhao et al . used a technique called tetraploid complementation, in which chimaeric mice are generated from injected pluripotent cells, and the embryonic tissue is derived solely from the injected cells. Boland et al . produced fertile adult mice derived entirely from iPS cells generated by inducible genetic reprogramming of mouse embryonic fibroblasts. The availability of these mice will provide a new resource for the study of iPS cell-derived tissues for both research and cell replacement therapy applications. Differentiated cells can be reprogrammed into induced pluripotent stem (iPS) cells through the transient overexpression of a small number of transcription factors. These iPS cells resemble embryonic stem (ES) cells but, until now, they had not passed the most stringent test of pluripotency by generating full-term or adult mice in tetraploid complementation assays. Here, fertile adult mice derived entirely from iPS cells are reported. Recent landmark experiments have shown that transient overexpression of a small number of transcription factors can reprogram differentiated cells into induced pluripotent stem (iPS) cells that resemble embryonic stem (ES) cells 1 , 2 , 3 , 4 , 5 , 6 , 7 . These iPS cells hold great promise for medicine because they have the potential to generate patient-specific cell types for cell replacement therapy and produce in vitro models of disease, without requiring embryonic tissues or oocytes 8 , 9 , 10 . Although current iPS cell lines resemble ES cells, they have not passed the most stringent test of pluripotency by generating full-term or adult mice in tetraploid complementation assays 3 , 11 , raising questions as to whether they are sufficiently potent to generate all of the cell types in an organism. Whether this difference between iPS and ES cells reflects intrinsic limitations of direct reprogramming is not known. Here we report fertile adult mice derived entirely from iPS cells that we generated by inducible genetic reprogramming of mouse embryonic fibroblasts. Producing adult mice derived entirely from a reprogrammed fibroblast shows that all features of a differentiated cell can be restored to an embryonic level of pluripotency without exposure to unknown ooplasmic factors. Comparing these fully pluripotent iPS cell lines to less developmentally potent lines may reveal molecular markers of different pluripotent states. Furthermore, mice derived entirely from iPS cells will provide a new resource to assess the functional and genomic stability of cells and tissues derived from iPS cells, which is important to validate their utility in cell replacement therapy and research applications.