Cloning from somatic cells is inefficient, with most clones dying during gestation1,2. Cloning from embryonic stem (ES) cells is much more effective, suggesting that the nucleus of an embryonic cell is easier to reprogram3,4,5,6,7. It is thus possible that most surviving clones are, in fact, derived from the nuclei of rare somatic stem cells present in adult tissues, rather than from the nuclei of differentiated cells, as has been assumed1,8,9. Here we report the generation of monoclonal mice by nuclear transfer from mature lymphocytes. In a modified two-step cloning procedure, we established ES cells from cloned blastocysts and injected them into tetraploid blastocysts to generate mice. In this approach, the embryo is derived from the ES cells and the extra-embryonic tissues from the tetraploid host6. Animals cloned from a B-cell nucleus were viable and carried fully rearranged immunoglobulin alleles in all tissues. Similarly, a mouse cloned from a T-cell nucleus carried rearranged T-cell-receptor genes in all tissues. This is an unequivocal demonstration that a terminally differentiated cell can be reprogrammed to produce an adult cloned animal.
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We thank W. Rideout, K. Eggan, D. Humpherys and Z. Wang for discussions on the project; S. Nguyen, V. Haase, T. Novobrantseva and C. J. Ryu for advice with immunological analyses and for Southern blot probes; J. Dausman and R. Flannery for animal care; and A. Chess, C. Beard and J. Gribnau for critical reading of the manuscript. K.H. was supported by a PhD fellowship from the Boehringer Ingelheim Fonds. Support to R.J. was from the National Cancer Institute.
The authors declare that they have no competing financial interests.
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Hochedlinger, K., Jaenisch, R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 415, 1035–1038 (2002). https://doi.org/10.1038/nature718
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