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De novo cardiomyocytes from within the activated adult heart after injury

Nature volume 474, pages 640–644 (2011)Cite this article

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Abstract

A significant bottleneck in cardiovascular regenerative medicine is the identification of a viable source of stem/progenitor cells that could contribute new muscle after ischaemic heart disease and acute myocardial infarction1. A therapeutic ideal—relative to cell transplantation—would be to stimulate a resident source, thus avoiding the caveats of limited graft survival, restricted homing to the site of injury and host immune rejection. Here we demonstrate in mice that the adult heart contains a resident stem or progenitor cell population, which has the potential to contribute bona fide terminally differentiated cardiomyocytes after myocardial infarction. We reveal a novel genetic label of the activated adult progenitors via re-expression of a key embryonic epicardial gene, Wilm’s tumour 1 (Wt1), through priming by thymosin β4, a peptide previously shown to restore vascular potential to adult epicardium-derived progenitor cells2 with injury. Cumulative evidence indicates an epicardial origin of the progenitor population, and embryonic reprogramming results in the mobilization of this population and concomitant differentiation to give rise to de novo cardiomyocytes. Cell transplantation confirmed a progenitor source and chromosome painting of labelled donor cells revealed transdifferentiation to a myocyte fate in the absence of cell fusion. Derived cardiomyocytes are shown here to structurally and functionally integrate with resident muscle; as such, stimulation of this adult progenitor pool represents a significant step towards resident-cell-based therapy in human ischaemic heart disease.

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Figure 1: Activated Wt1 + cells give rise to cardiac progenitors in the injured adult heart.
Figure 2: Activated adult Wt1 + progenitors differentiate into structurally coupled cardiomyocytes.
Figure 3: Prospective donor Wt1 + /GFP + cells at day 4 after myocardial infarction seem to be derived from epicardium.
Figure 4: Transplanted donor Wt1 + progenitors differentiate into cardiomyocytes within host myocardium in the absence of cell fusion.

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References

  1. Willems, E., Bushway, P. J. & Mercola, M. Natural and synthetic regulators of embryonic stem cell cardiogenesis. Pediatr. Cardiol. 30, 635–642 (2009)

    Article  Google Scholar 

  2. Smart, N. et al. Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization. Nature 445, 177–182 (2007)

    Article  ADS  CAS  Google Scholar 

  3. Cai, C. L. et al. A myocardial lineage derives from Tbx18 epicardial cells. Nature 454, 104–108 (2008)

    Article  ADS  CAS  Google Scholar 

  4. Zhou, B. et al. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454, 109–113 (2008)

    Article  ADS  CAS  Google Scholar 

  5. Christoffels, V. M. et al. Tbx18 and the fate of epicardial progenitors. Nature 458, E8–E9 (2009)

    Article  ADS  CAS  Google Scholar 

  6. Bock-Marquette, I. et al. Thymosin β4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo . J. Mol. Cell. Cardiol. 46, 728–738 (2009)

    Article  CAS  Google Scholar 

  7. Smart, N. & Riley, P. R. Derivation of epicardium-derived progenitor cells (EPDCs) from adult epicardium. Curr. Protoc. Stem Cell Biol. Unit 2C.2. (2009)

  8. Laugwitz, K. L. et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005)

    Article  ADS  CAS  Google Scholar 

  9. Moretti, A. et al. Multipotent embryonic Isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 127, 1151–1165 (2006)

    Article  CAS  Google Scholar 

  10. Wu, S. M. et al. Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell 127, 1137–1150 (2006)

    Article  CAS  Google Scholar 

  11. Prall, O. W. et al. An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell 128, 947–959 (2007)

    Article  CAS  Google Scholar 

  12. Limana, F. et al. Myocardial infarction induces embryonic reprogramming of epicardial c-kit+ cells: role of the pericardial fluid. J. Mol. Cell. Cardiol. 48, 609–618 (2010)

    Article  CAS  Google Scholar 

  13. Rubart, M. et al. Two-photon molecular excitation imaging of Ca2+ transients in Langendorff-perfused mouse hearts. Am. J. Physiol. Cell Physiol. 284, C1654–C1668 (2003)

    Article  CAS  Google Scholar 

  14. Mahtab, E. A. et al. Cardiac malformations and myocardial abnormalities in podoplanin knockout mouse embryos: correlation with abnormal epicardial development. Dev. Dyn. 237, 847–857 (2008)

    Article  CAS  Google Scholar 

  15. Chen, J., Kubalak, S. W. & Chien, K. R. Ventricular muscle-restricted targeting of the RXRα gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. Development 125, 1943–1949 (1998)

    CAS  PubMed  Google Scholar 

  16. Wagner, K. D. et al. The Wilms’ tumor suppressor Wt1 is expressed in the coronary vasculature after myocardial infarction. FASEB J. 16, 1117–1119 (2002)

    Article  CAS  Google Scholar 

  17. Bock-Marquette, I. et al. Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432, 466–472 (2004)

    Article  ADS  CAS  Google Scholar 

  18. Smart, N. et al. Thymosin β4 facilitates epicardial neovascularization of the injured adult heart. Ann. N. Y. Acad. Sci. 1194, 97–104 (2010)

    Article  ADS  CAS  Google Scholar 

  19. Rubart, M. et al. Two-photon molecular excitation imaging of Ca2+ transients in Langendorff-perfused mouse hearts. Am. J. Physiol. Cell Physiol. 284, C1654–C1668 (2003)

    Article  CAS  Google Scholar 

  20. Ieda, M. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010)

    Article  CAS  Google Scholar 

  21. Moorman, A. F. et al. Sensitive nonradioactive detection of mRNA in tissue sections: novel application of the whole-mount in situ hybridization protocol. J. Histochem. Cytochem. 49, 1–8 (2001)

    Article  CAS  Google Scholar 

  22. Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25, 402–408 (2001)

    Article  CAS  Google Scholar 

  23. Price, A. et al. Late gadolinium enhanced MRI in small animal models of myocardial infarction. J. Cardiovasc. Magn. Reson. 12 (Suppl. 1). P98 (2010)

    Article  Google Scholar 

  24. Heiberg, E. et al. Time resolved three-dimensional automated segmentation of the left ventricle. Comput. Cardiol. 32, 599–602 (2005)

    Google Scholar 

  25. Ihaka, R. & Gentleman, R. R: a language for data analysis and graphics. J. Comput. Graph. Stat. 5, 299–314 (1996)

    Google Scholar 

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Acknowledgements

This work was funded by the British Heart Foundation. We are grateful to F. Costantini and S. Srinivas for providing the R26R–EYFP mouse strain, to B. Vernay for assistance with confocal microscopy and A. Eddaoudi, P. Chana and A. Angheluta for assistance in flow cytometry. We thank A. Taylor and V. Muthurangu for functional interpretation of MRI data and RegeneRx Biopharmaceuticals for provision of clinical grade Tβ4.

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Author notes

  1. Nicola Smart and Sveva Bollini: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, UK ,

    Nicola Smart, Sveva Bollini, Karina N. Dubé, Joaquim M. Vieira & Paul R. Riley

  2. Harvard Stem Cell Institute and Department of Cardiology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA,

    Bin Zhou & William T. Pu

  3. Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA,

    Bin Zhou & William T. Pu

  4. Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 20031, China

    Bin Zhou

  5. The Hatter Cardiovascular Institute, University College London, London WC1E 6HX, USA ,

    Sean Davidson & Derek Yellon

  6. Department of Medicine and Institute of Child Health, Centre for Advanced Biomedical Imaging (CABI), University College London, London WC1E 6DD, UK,

    Johannes Riegler & Mark F. Lythgoe

  7. Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, UK ,

    Johannes Riegler

  8. MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, UK ,

    Anthony N. Price

Authors
  1. Nicola Smart
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  2. Sveva Bollini
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  10. Mark F. Lythgoe
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  11. William T. Pu
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  12. Paul R. Riley
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Contributions

N.S. carried out the in vivo histological assessments of cardiomyocytes and FISH experiments. S.B. carried out the explant and FACS studies and jointly with K.N.D. established the myocardial infarction model and the cell transplantation. J.M.V. carried out the qRT–PCR analyses and assisted with cell transplantation. B.Z. generated the Wt1GFPCre and Wt1CreERT2 mice. S.D. and D.Y. performed the two-photon microscopy and Ca2+ transient recordings. J.R., A.N.P. and M.F.L. carried out the MRI functional analyses. W.T.P. provided the Wt1GFPCre and Wt1CreERT2 mice. P.R.R. established the hypotheses and experimental design, co-analysed data and wrote the manuscript.

Corresponding author

Correspondence to Paul R. Riley.

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The authors declare no competing financial interests.

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The file contains Supplementary Figures 1-11 with legends. Supplementary Table 1 was added on June 30th 2011. (PDF 1166 kb)

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Smart, N., Bollini, S., Dubé, K. et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature 474, 640–644 (2011). https://doi.org/10.1038/nature10188

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