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Adult mice generated from induced pluripotent stem cells


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) cells1,2,3,4,5,6,7. 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 oocytes8,9,10. 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 assays3,11, 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.

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Figure 1: Generation of iPS cells.
Figure 2: Adult mice derived from iMZ cell lines.
Figure 3: Genetic analyses of iPS mice.

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We wish to thank S. Carlson for help with animal husbandry, K. Spencer for help with imaging, and D. Trajkovic for help with histology. We thank G. Joyce, U. Mueller, L. Stowers, A. Patapoutian and A. Maximov for critical reading of the manuscript. We thank M. Mayford for the gift of rtTAM2.2, A. Maximov for the lentiviral vector backbones, and members of A. Kralli’s laboratory for assistance with qPCR. We thank R. Axel for supporting the generation of the Pcdh21/Cre mouse strain, which was a gift. This work was supported by a Pew Scholars Award (K.K.B.) and grants from the California Institute of Regenerative Medicine, the Whitehall Foundation, the O’Keefe Foundation, and the Shapiro Family Foundation.

Author Contributions M.J.B., J.L.H. and K.L.N. designed and performed experiments, analysed data and edited the manuscript. A.R.R. performed blastocyst injections, Caesarean sections and cross fostering. W.G. assisted in designing and generating lentiviral constructs. G.M. assisted with cell culture. S.K. designed and performed experiments, analysed data and edited the manuscript. K.K.B. conceived of the experimental design, performed experiments, analysed data and wrote the manuscript.

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Correspondence to Kristopher L. Nazor or Kristin K. Baldwin.

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Boland, M., Hazen, J., Nazor, K. et al. Adult mice generated from induced pluripotent stem cells. Nature 461, 91–94 (2009).

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