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Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts

Nature Biotechnology volume 25, pages 10151024 (2007) | Download Citation

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Abstract

Cardiomyocytes derived from human embryonic stem (hES) cells potentially offer large numbers of cells to facilitate repair of the infarcted heart. However, this approach has been limited by inefficient differentiation of hES cells into cardiomyocytes, insufficient purity of cardiomyocyte preparations and poor survival of hES cell–derived myocytes after transplantation. Seeking to overcome these challenges, we generated highly purified human cardiomyocytes using a readily scalable system for directed differentiation that relies on activin A and BMP4. We then identified a cocktail of pro-survival factors that limits cardiomyocyte death after transplantation. These techniques enabled consistent formation of myocardial grafts in the infarcted rat heart. The engrafted human myocardium attenuated ventricular dilation and preserved regional and global contractile function after myocardial infarction compared with controls receiving noncardiac hES cell derivatives or vehicle. The ability of hES cell–derived cardiomyocytes to partially remuscularize myocardial infarcts and attenuate heart failure encourages their study under conditions that closely match human disease.

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Acknowledgements

The authors thank Lil Pabon for helpful scientific discussions and Vasily Yarnykh and Eric Shankland for support of our magnetic resonance imaging studies. We are indebted to Kellii Schurb for assistance with animal surgery, to Mark Saiget for assistance with ALU qPCR and to Ron Hanson for managerial support of the project. We thank Jane Lebkowski for her ongoing support of this research collaboration. We thank K. Chien for myosin light chain 2V, rabbit polyclonal. This study was supported in part by a grant from Geron and in part by National Institutes of Health grants P01 HL03174, R01 HL061553, R01 HL084642, P20 GM069983 (to C.E.M.), R24 HL064387 (to C.E.M. and M.A.L.), T32 HL07828 (to M.A.L. and K.Y.C.), K08 HL080431 (to M.A.L.) and T32 EB001650 (to A.V.N.).

Author information

Author notes

    • Michael A Laflamme
    •  & Kent Y Chen

    These authors contributed equally to this work.

Affiliations

  1. Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, 815 Mercer Street, Seattle, Washington 98109, USA.

    • Michael A Laflamme
    • , Kent Y Chen
    • , Anna V Naumova
    • , Veronica Muskheli
    • , James A Fugate
    • , Sarah K Dupras
    • , Hans Reinecke
    • , Elina Minami
    • , Shuichi Ueno
    • , Chun Yuan
    •  & Charles E Murry
  2. Department of Pathology, University of Washington, 815 Mercer Street, Seattle, Washington 98109, USA.

    • Michael A Laflamme
    • , Kent Y Chen
    • , Veronica Muskheli
    • , James A Fugate
    • , Sarah K Dupras
    • , Hans Reinecke
    • , Shuichi Ueno
    •  & Charles E Murry
  3. Department of Medicine/Cardiology, University of Washington, 1959 NE Pacific Street, Seattle, Washington 98195, USA.

    • Kent Y Chen
    • , Elina Minami
    •  & Edward A Gill
  4. Vascular Imaging Laboratory, Department of Radiology, University of Washington, 815 Mercer Street, Seattle, Washington 98109, USA.

    • Anna V Naumova
    •  & Chun Yuan
  5. Geron Corporation, 230 Constitution Drive, Menlo Park, California 94025, USA.

    • Chunhui Xu
    • , Mohammad Hassanipour
    • , Shailaja Police
    • , Chris O'Sullivan
    • , Lila Collins
    • , Yinhong Chen
    •  & Joseph Gold

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Contributions

M.A.L. and K.Y.C. were the principal experimentalists and contributed to the writing of the manuscript. A.V.N. performed the MRI scans and contributed to the writing. V.M. performed most of the histology and microscopy. J.A.F. cultured hES-derived cardiomyocytes and prepared cells for transplant. S.K.D. performed surgeries and in situ hybridization. H.R. performed the biodistribution studies. C.X., M.H., S.P., C.O., L.C. and J.G. generated hES-derived cardiomyocytes and prepared cells for transplant. Y.C. performed surgeries. E.M., E.A.G. and S.U. performed the echocardiography. J.G. designed experiments and contributed to the writing of the manuscript. C.Y. coordinated the MRI studies. C.E.M. designed experiments, coordinated the project and contributed to the writing of the manuscript.

Competing interests

There is a sponsored research agreement between Geron Corporation (co-investigators on this study) and the Murry laboratory.

Corresponding author

Correspondence to Charles E Murry.

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https://doi.org/10.1038/nbt1327