Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Differentiated cells are more efficient than adult stem cells for cloning by somatic cell nuclear transfer


Since the creation of Dolly via somatic cell nuclear transfer (SCNT)1, more than a dozen species of mammals have been cloned using this technology2. One hypothesis for the limited success of cloning via SCNT (1%–5%)3 is that the clones are likely to be derived from adult stem cells4. Support for this hypothesis comes from the findings that the reproductive cloning efficiency for embryonic stem cells is five to ten times higher than that for somatic cells as donors5,6 and that cloned pups cannot be produced directly from cloned embryos derived from differentiated B and T cells or neuronal cells7,8,9,10. The question remains as to whether SCNT-derived animal clones can be derived from truly differentiated somatic cells. We tested this hypothesis with mouse hematopoietic cells at different differentiation stages: hematopoietic stem cells, progenitor cells and granulocytes. We found that cloning efficiency increases over the differentiation hierarchy, and terminally differentiated postmitotic granulocytes yield cloned pups with the greatest cloning efficiency.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Different hematopoietic cell subsets used in our nuclear transfer experiments.
Figure 2: Development of cloned embryos reconstructed with purified granulocytes.
Figure 3: Functional characterization of the hematopoietic stem and progenitor cell populations from the BDF1 mice.
Figure 4: Global gene expression profiling analysis of different hematopoietic cells.

Accession codes


Gene Expression Omnibus


  1. Wilmut, I., Schnieke, A.E., McWhir, J., Kind, A.J. & Campbell, K.H. Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813 (1997).

    Article  CAS  Google Scholar 

  2. Tian, X.C., Kubota, C., Enright, B. & Yang, X. Cloning animals by somatic cell nuclear transfer–biological factors. Reprod. Biol. Endocrinol. 1, 98 (2003).

    Article  Google Scholar 

  3. Yanagimachi, R. Cloning: experience from the mouse and other animals. Mol. Cell. Endocrinol. 187, 241–248 (2002).

    Article  CAS  Google Scholar 

  4. Hochedlinger, K. & Jaenisch, R. Nuclear transplantation: lessons from frogs and mice. Curr. Opin. Cell Biol. 14, 741–748 (2002).

    Article  CAS  Google Scholar 

  5. Rideout, W.M., III, Eggan, K. & Jaenisch, R. Nuclear cloning and epigenetic reprogramming of the genome. Science 293, 1093–1098 (2001).

    Article  CAS  Google Scholar 

  6. Humpherys, D. et al. Epigenetic instability in ES cells and cloned mice. Science 293, 95–97 (2001).

    Article  CAS  Google Scholar 

  7. Eggan, K. et al. Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc. Natl. Acad. Sci. USA 98, 6209–6214 (2001).

    Article  CAS  Google Scholar 

  8. Eggan, K. et al. Mice cloned from olfactory sensory neurons. Nature 428, 44–49 (2004).

    Article  CAS  Google Scholar 

  9. Li, J., Ishii, T., Feinstein, P. & Mombaerts, P. Odorant receptor gene choice is reset by nuclear transfer from mouse olfactory sensory neurons. Nature 428, 393–399 (2004).

    Article  CAS  Google Scholar 

  10. Hochedlinger, K. & Jaenisch, R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 415, 1035–1038 (2002).

    Article  CAS  Google Scholar 

  11. Weissman, I.L., Anderson, D.J. & Gage, F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu. Rev. Cell Dev. Biol. 17, 387–403 (2001).

    Article  CAS  Google Scholar 

  12. Yu, H., Yuan, Y., Shen, H. & Cheng, T. Hematopoietic stem cell exhaustion impacted by p18 INK4C and p21 Cip1/Waf1 in opposite manners. Blood 107, 1200–1206 (2006).

    Article  CAS  Google Scholar 

  13. Yuan, Y., Shen, H., Franklin, D.S., Scadden, D.T. & Cheng, T. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nat. Cell Biol. 6, 436–442 (2004).

    Article  CAS  Google Scholar 

  14. Smith, A.L., Ellison, F.M., McCoy, J.P., Jr. & Chen, J. c-Kit expression and stem cell factor-induced hematopoietic cell proliferation are up-regulated in aged B6D2F1 mice. J. Gerontol. A Biol. Sci. Med. Sci. 60, 448–456 (2005).

    Article  Google Scholar 

  15. Wakayama, T., Perry, A.C., Zuccotti, M., Johnson, K.R. & Yanagimachi, R. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394, 369–374 (1998).

    Article  CAS  Google Scholar 

  16. Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996).

    Article  CAS  Google Scholar 

  17. Inoue, K. et al. Inefficient reprogramming of the hematopoietic stem cell genome following nuclear transfer. J. Cell Sci. 119, 1985–1991 (2006).

    Article  CAS  Google Scholar 

  18. Gao, S., McGarry, M., Latham, K.E. & Wilmut, I. Cloning of mice by nuclear transfer. Cloning Stem Cells 5, 287–294 (2003).

    Article  CAS  Google Scholar 

  19. Gao, S. et al. Effect of cell confluence on production of cloned mice using an inbred embryonic stem cell line. Biol. Reprod. 68, 595–603 (2003).

    Article  CAS  Google Scholar 

  20. Takano, H., Ema, H., Sudo, K. & Nakauchi, H. Asymmetric division and lineage commitment at the level of hematopoietic stem cells: inference from differentiation in daughter cell and granddaughter cell pairs. J. Exp. Med. 199, 295–302 (2004).

    Article  CAS  Google Scholar 

  21. Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R.C. & Melton, D.A. “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298, 597–600 (2002).

    Article  CAS  Google Scholar 

  22. Li, J., Ishii, T., Wen, D. & Mombaerts, P. Non-equivalence of cloned and clonal mice. Curr. Biol. 15, R756–R757 (2005).

    Article  CAS  Google Scholar 

  23. Inoue, K. et al. Generation of cloned mice by direct nuclear transfer from natural killer T cells. Curr. Biol. 15, 1114–1118 (2005).

    Article  CAS  Google Scholar 

  24. Smyth, M.J. et al. Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer. J. Exp. Med. 201, 1973–1985 (2005).

    Article  CAS  Google Scholar 

  25. Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21(cip1/waf1). Science 287, 1804–1808 (2000).

    Article  CAS  Google Scholar 

  26. Campbell, K.H. Nuclear equivalence, nuclear transfer, and the cell cycle. Cloning 1, 3 (1999).

    Article  CAS  Google Scholar 

  27. Ivanova, N.B. et al. A stem cell molecular signature. Science 298, 601–604 (2002).

    Article  CAS  Google Scholar 

  28. Molofsky, A.V., Pardal, R. & Morrison, S.J. Diverse mechanisms regulate stem cell self-renewal. Curr. Opin. Cell Biol. 16, 700–707 (2004).

    Article  CAS  Google Scholar 

  29. Wagers, A.J., Sherwood, R.I., Christensen, J.L. & Weissman, I.L. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297, 2256–2259 (2002).

    Article  CAS  Google Scholar 

  30. Blelloch, R. et al. Reprogramming efficiency following somatic cell nuclear transfer is influenced by the differentiation and methylation state of the donor nucleus. Stem Cells 24, 2007–2013 (2006).

    Article  CAS  Google Scholar 

Download references


We thank M. Watanabe for careful reading and editing of our manuscript. This work was funded by US Department of Agriculture–Agricultural Research Service (USDA-ARS) contract numbers AG 58-1265-2-018 and 58-1265-2-020 as well as the Cooperative State Research, Education, and Extension Service (CSREES)-USDA and the Storrs Agricultural Experiment Station (X.Y. and X.T.), US National Institutes of Health grant HL70561 (T.C.) and the Scholar Award from the American Society of Hematology (T.C.).

Author information

Authors and Affiliations



This study was designed and overseen by X.Y and T.C.; nuclear transfer, characterization of the cloned embryos and data analyses were performed by L.S., S.G., C.C., L.K and X.T; hematopoietic cell isolation and functional assessments were done by H.S., H.Y. and Y.S.; gene expression profiling was performed and analyzed by L.S., S.S., D.T., K.I., J.L, A.L. and S.W.; and T.C., X.Y., S.G. L.S and S.S. contributed to the writing of the paper.

Corresponding authors

Correspondence to Xiangzhong Yang or Tao Cheng.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sung, LY., Gao, S., Shen, H. et al. Differentiated cells are more efficient than adult stem cells for cloning by somatic cell nuclear transfer. Nat Genet 38, 1323–1328 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing