Article | Published:

Stimulus-triggered fate conversion of somatic cells into pluripotency

Nature volume 505, pages 641647 (30 January 2014) | Download Citation



Here we report a unique cellular reprogramming phenomenon, called stimulus-triggered acquisition of pluripotency (STAP), which requires neither nuclear transfer nor the introduction of transcription factors. In STAP, strong external stimuli such as a transient low-pH stressor reprogrammed mammalian somatic cells, resulting in the generation of pluripotent cells. Through real-time imaging of STAP cells derived from purified lymphocytes, as well as gene rearrangement analysis, we found that committed somatic cells give rise to STAP cells by reprogramming rather than selection. STAP cells showed a substantial decrease in DNA methylation in the regulatory regions of pluripotency marker genes. Blastocyst injection showed that STAP cells efficiently contribute to chimaeric embryos and to offspring via germline transmission. We also demonstrate the derivation of robustly expandable pluripotent cell lines from STAP cells. Thus, our findings indicate that epigenetic fate determination of mammalian cells can be markedly converted in a context-dependent manner by strong environmental cues.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962)

  2. 2.

    , , , & Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394, 369–374 (1998)

  3. 3.

    & Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006)

  4. 4.

    History of plant tissue culture. Mol. Biotechnol. 37, 169–180 (2007)

  5. 5.

    et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49 (2002)

  6. 6.

    et al. Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J. Cell Sci. 117, 2971–2981 (2004)

  7. 7.

    et al. A population of very small embryonic-like (VSEL) CXCR4+SSEA-1+Oct-4+ stem cells identified in adult bone marrow. Leukemia 20, 857–869 (2006)

  8. 8.

    et al. Unique multipotent cells in adult human mesenchymal cell populations. Proc. Natl Acad. Sci. USA 107, 8639–8643 (2010)

  9. 9.

    et al. The potential of stem cells in adult tissues representative of the three germ layers. Tissue Eng. Part A 17, 607–615 (2011)

  10. 10.

    , & The pluripotency regulator Oct4: a role in somatic stem cells? Cell Cycle 7, 725–728 (2008)

  11. 11.

    & An argument against a role for Oct4 in somatic stem cells. Cell Stem Cell 1, 359–360 (2007)

  12. 12.

    et al. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460, 1132–1135 (2009)

  13. 13.

    et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133, 250–264 (2008)

  14. 14.

    et al. Identification and characterization of stem cells in prepubertal spermatogenesis in mice small star, filled. Dev. Biol. 258, 209–225 (2003)

  15. 15.

    Neural induction in explants which have passed through a sublethal cytolysis. J. Exp. Zool. 106, 197–222 (1947)

  16. 16.

    Johannes Holtfreter’s contributions to ongoing studies of the organizer. Dev. Dyn. 205, 245–256 (1996)

  17. 17.

    Ernest Everett Just, Johannes Holtfreter, and the origin of certain concepts in embryo morphogenesis. Mol. Reprod. Dev. 76, 912–921 (2009)

  18. 18.

    , & Flow cytometric enumeration and immunophenotyping of hematopoietic stem and progenitor cells. Semin. Hematol. 38, 139–147 (2001)

  19. 19.

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

  20. 20.

    et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008)

  21. 21.

    et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448, 196–199 (2007)

  22. 22.

    et al. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448, 191–195 (2007)

  23. 23.

    et al. Isolation, culture and evaluation of multilineage-differentiating stress-enduring (Muse) cells. Nature Protocols 8, 1391–1415 (2013)

  24. 24.

    How is pluripotency determined and maintained? Development 134, 635–646 (2007)

  25. 25.

    et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nature Neurosci. 8, 288–296 (2005)

  26. 26.

    et al. Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28, 31–40 (2000)

  27. 27.

    et al. BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nature Biotechnol. 24, 1402–1411 (2006)

  28. 28.

    & Lonely death dance of human pluripotent stem cells: ROCKing between metastable cell states. Trends Cell Biol. 21, 274–282 (2011)

  29. 29.

    et al. Molecular pathway and cell state responsible for dissociation-induced apoptosis in human embryonic stem cells. Cell Stem Cell 7, 225–239 (2010)

  30. 30.

    , , , & Choice of random rather than imprinted X inactivation in female embryonic stem cell-derived extra-embryonic cells. Development 138, 197–202 (2011)

  31. 31.

    & Extrinsic regulation of pluripotent stem cells. Nature 465, 713–720 (2010)

  32. 32.

    & Development of gynogenetic eggs in the mouse: implications for parthenogenetic embryos. Science 222, 1034–1036 (1983)

  33. 33.

    et al. Successful serial recloning in the mouse over multiple generations. Cell Stem Cell 12, 293–297 (2013)

  34. 34.

    , , , & Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428 (1993)

  35. 35.

    , , & Developmental potential and behavior of tetraploid cells in the mouse embryo. Dev. Biol. 288, 150–159 (2005)

  36. 36.

    , , & A novel mechanism for regulating clonal propagation of mouse ES cells. Genes Cells 9, 471–477 (2004)

  37. 37.

    & Neural induction in the absence of organizer in salamander is mediated by MAPK. Dev. Biol. 307, 282–289 (2007)

  38. 38.

    et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341, 651–654 (2013)

  39. 39.

    et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011)

  40. 40.

    , & Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 457, 896–900 (2009)

  41. 41.

    , , & Seven-fluorochrome mouse M-FISH for high-resolution analysis of interchromosomal rearrangements. Cytogenet. Genome Res. 103, 84–88 (2003)

Download references


We thank S. Nishikawa for discussion and J. D. Ross, N. Takata, M. Eiraku, M. Ohgushi, S. Itoh, S. Yonemura, S. Ohtsuka and K. Kakiguchi for help with experiments and analyses. We thank A. Penvose and K. Westerman for comments on the manuscript. H.O. is grateful to T. Okano, S. Tsuneda and K. Kuroda for support and encouragement. Financial support for this research was provided by Intramural RIKEN Research Budget (H.O., T.W. and Y.S.), a Scientific Research in Priority Areas (20062015) to T.W., the Network Project for Realization of Regenerative Medicine to Y.S., and Department of Anesthesiology, Perioperative and Pain Medicine at Brigham and Women’s Hospital to C.A.V.

Author information

Author notes

    • Teruhiko Wakayama

    Present address: Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan.


  1. Laboratory for Tissue Engineering and Regenerative Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Haruko Obokata
    • , Koji Kojima
    • , Martin P. Vacanti
    •  & Charles A. Vacanti
  2. Laboratory for Cellular Reprogramming, RIKEN Center for Developmental biology, Kobe 650-0047, Japan

    • Haruko Obokata
  3. Laboratory for Genomic Reprogramming, RIKEN Center for Developmental biology, Kobe 650-0047, Japan

    • Haruko Obokata
    •  & Teruhiko Wakayama
  4. Laboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental biology, Kobe 650-0047, Japan

    • Yoshiki Sasai
  5. Department of Pathology, Irwin Army Community Hospital, Fort Riley, Kansas 66442, USA

    • Martin P. Vacanti
  6. Laboratory for Pluripotent Stem Cell Studies, RIKEN Center for Developmental biology, Kobe 650-0047, Japan

    • Hitoshi Niwa
  7. Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo 162-8666, Japan

    • Masayuki Yamato


  1. Search for Haruko Obokata in:

  2. Search for Teruhiko Wakayama in:

  3. Search for Yoshiki Sasai in:

  4. Search for Koji Kojima in:

  5. Search for Martin P. Vacanti in:

  6. Search for Hitoshi Niwa in:

  7. Search for Masayuki Yamato in:

  8. Search for Charles A. Vacanti in:


H.O. and Y.S. wrote the manuscript. H.O., T.W. and Y.S. performed experiments, and K.K. assisted with H.O.’s transplantation experiments. H.O., T.W., Y.S., H.N. and C.A.V. designed the project. M.P.V. and M.Y. helped with the design and evaluation of the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Haruko Obokata or Charles A. Vacanti.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Table 1.


  1. 1.

    Live imaging of low-pH-treated CD45+cells

    DIC images during day 0 – day 7, overlaid with oct3/4::GFP (green). A strong contrast of DIC (as compared to video 2) was applied to imaging so that lamellipodia-like processes (frequently seen on and after day 4) could be viewed easily.

  2. 2.

    Live imaging of low-pH-treated CD45+cells (another view)

    DIC images during day 0 – day 6, overlaid with oct3/4::GFP (green). The interval of imaging was half (15 min) of that of video 1 (the overall speed of the video is three-times slower than video 1). In this view field where the cell density was relatively low, behaviours of individual cells were more easily seen. In this case, forming clusters were slightly smaller in size.

  3. 3.

    STAP cell-derived embryo (E10.5) from 4N blastocyst injection

    STAP cells with constitutive GFP expression were injected into 4N blastocysts and produced normal embryos with heart beating.

  4. 4.

    Beating cardiac muscle generated from STAP-SCs in vitro Bright-field image.

About this article

Publication history





Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.