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Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells

Nature Biotechnology volume 23, pages 607–611 (2005)Cite this article

A Corrigendum to this article was published on 01 July 2005

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Abstract

Embryonic stem (ES) cells are a promising source of cardiomyocytes, but clinical application of ES cells has been hindered by the lack of reliable selective differentiation methods. Differentiation into any lineage is partly dependent on the regulatory mechanisms of normal early development. Although several signals, including bone morphogenetic protein (BMP)1,2, Wnt3 and FGF4, are involved in heart development, scarce evidence is available about the exact signals that mediate cardiomyocyte differentiation. While investigating the involvement of BMP signaling in early heart formation in the mouse, we found that the BMP antagonist Noggin is transiently but strongly expressed in the heart-forming region during gastrulation and acts at the level of induction of mesendoderm to establish conditions conducive to cardiogenesis. We applied this finding to develop an effective protocol for obtaining cardiomyocytes from mouse ES cells by inhibition of BMP signaling.

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Figure 1: Transient expression of noggin at the heart forming area.
Figure 2: Protocol and efficiency of the cardiomyocyte induction from ES cells using noggin, chordin and soluble BMP receptor-1A.
Figure 3: Expression of stem cell marker, cardiac transcription factors and cardiac specific proteins in noggin-treated ES cells.

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  • 01 July 2005

    Nat. Biotechnol. 23, 607–611 (2005) The order of the authors is incorrect. The correct order is: Shinsuke Yuasa, Yuji Itabashi, Uichi Koshimizu, Tomofumi Tanaka, Keijiro Sugimura, Masayoshi Kinoshita, Fumiyuki Hattori, Shin-ichi Fukami, Takuya Shimazaki, Satoshi Ogawa, Hideyuki Okano & Keiichi Fukuda.

References

  1. Winnier, G., Blessing, M., Labosky, P.A. & Hogan, B.L. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 9, 2105–2116 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Zhang, H. & Bradley, A. Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122, 2977–2986 (1996).

    CAS  PubMed  Google Scholar 

  3. Marvin, M.J., Di Rocco, G., Gardiner, A., Bush, S.M. & Lassar, A.B. Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes Dev. 15, 316–327 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mima, T., Ueno, H., Fischman, D.A., Williams, L.T. & Mikawa, T. Fibroblast growth factor receptor is required for in vivo cardiac myocyte proliferation at early embryonic stages of heart development. Proc. Natl. Acad. Sci. USA 92, 467–471 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sasai, Y., Lu, B., Steinbeisser, H. & De Robertis, E.M. Regulation of neural induction by the Chd and Bmp-4 antagonistic patterning signals in Xenopus. Nature 376, 333–336 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Lim, D.A. et al. A. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713–726 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Smith, W.C. & Harland, R.M. Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell 70, 829–840 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. McMahon, J.A. et al. Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev. 12, 1438–1452 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kubo, A. et al. Development of definitive endoderm from embryonic stem cells in culture. Development 131, 1651–1662 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Sauer, H., Rahimi, G., Hescheler, J. & Wartenberg, M. Role of reactive oxygen species and phosphatidylinositol 3-kinase in cardiomyocyte differentiation of embryonic stem cells. FEBS Lett. 476, 218–223 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Behfar, A. et al. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J. 16, 1558–1566 (2002).

    Article  PubMed  Google Scholar 

  12. Schroeder, T. et al. Recombination signal sequence-binding protein Jkappa alters mesodermal cell fate decisions by suppressing cardiomyogenesis. Proc. Natl. Acad. Sci. USA 100, 4018–4023 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Takahashi, T. et al. Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 107, 1912–1916 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Boheler, K.R. et al. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ. Res. 91, 189–201 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Heng, B.C., Haider, H.K., Sim, E.K., Cao, T. & Ng, S.C. Strategies for directing the differentiation of stem cells into the cardiomyogenic lineage in vitro. Cardiovasc. Res. 62, 34–42 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Sachinidis, A. et al. Cardiac specific differentiation of mouse embryonic stem cells. Cardiovasc. Res. 58, 278–291 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Schultheiss, T.M., Burch, J.B. & Lassar, A.B. A role for bone morphogenetic proteins in the induction of cardiac myogenesis. Genes Dev. 11, 451–462 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Andree, B., Duprez, D., Vorbusch, B., Arnold, H.H. & Brand, T. BMP-2 induces ectopic expression of cardiac lineage markers and interferes with somite formation in chicken embryos. Mech. Dev. 70, 119–131 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Ladd, A.N., Yatskievych, T.A. & Antin, P.B. Regulation of avian cardiac myogenesis by activin/TGFbeta and bone morphogenetic proteins. Dev. Biol. 204, 407–419 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Lyons, K.M., Hogan, B.L. & Robertson, E.J. Colocalization of BMP 7 and BMP 2 RNAs suggests that these factors cooperatively mediate tissue interactions during murine development. Mech. Dev. 50, 71–83 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Lim, D.A. et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713–726 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Smith, W.C., Knecht, A.K., Wu, M. & Harland, R.M. Secreted noggin protein mimics the Spemann organizer in dorsalizing Xenopus mesoderm. Nature 361, 547–549 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Lamb, T.M. et al. Neural induction by the secreted polypeptide noggin. Science 262, 713–718 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Zimmerman, L.B., De Jesus-Escobar, J.M. & Harland, R.M. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86, 599–606 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Liem, K.F. Jr., Jessell, T.M. & Briscoe, J. Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites. Development 127, 4855–4866 (2000).

    CAS  PubMed  Google Scholar 

  26. Winnier, G., Blessing, M., Labosky, P.A. & Hogan, B.L. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 9, 2105–2116 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Sasaki, H. & Hogan, B.L. Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. Development 118, 47–59 (1993).

    CAS  PubMed  Google Scholar 

  28. Niwa, H., Miyazaki, J. & Smith, A.G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat. Genet. 24, 372–376 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. USA 90, 8424–8428 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature 326, 292–295 (1987).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was (partially) supported by a grant-in-aid from the 21st century Center of Excellence Program of the Ministry of Education, Culture, Sports, Science and Technology, Japan to Keio University. We are grateful to H. Niwa for kindly providing ES cell line EB3 and T. Yoshizaki and Y. Okada for their thoughtful advice and discussion.

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Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Shinsuke Yuasa, Yuji Itabashi, Masayoshi Kinoshita & Satoshi Ogawa

  2. Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Shinsuke Yuasa, Fumiyuki Hattori & Keiichi Fukuda

  3. Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Shin-ichi Fukami, Takuya Shimazaki & Hideyuki Okano

  4. Daiichi Suntory Biomedical Research Co. Ltd., 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka, 618–8513, Japan

    Uichi Koshimizu, Tomofumi Tanaka, Keijiro Sugimura & Fumiyuki Hattori

  5. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, 332-0012, Saitama, Japan

    Hideyuki Okano

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  1. Shinsuke Yuasa
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Correspondence to Keiichi Fukuda.

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Supplementary information

Supplementary Fig. 1

Dose-efficiency relationship of Noggin administration was demonstrated using R1 ES cell lines. (PDF 89 kb)

Supplementary Table 1

PCR primers used in this study (PDF 50 kb)

Supplementary Video

Noggin-treated beating embryoid body (MOV 2592 kb)

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Yuasa, S., Itabashi, Y., Koshimizu, U. et al. Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells. Nat Biotechnol 23, 607–611 (2005). https://doi.org/10.1038/nbt1093

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