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Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation

Nature volume 464, pages 606–609 (2010)Cite this article

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Abstract

Although mammalian hearts show almost no ability to regenerate, there is a growing initiative to determine whether existing cardiomyocytes or progenitor cells can be coaxed into eliciting a regenerative response. In contrast to mammals, several non-mammalian vertebrate species are able to regenerate their hearts1,2,3, including the zebrafish4,5, which can fully regenerate its heart after amputation of up to 20% of the ventricle. To address directly the source of newly formed cardiomyocytes during zebrafish heart regeneration, we first established a genetic strategy to trace the lineage of cardiomyocytes in the adult fish, on the basis of the Cre/lox system widely used in the mouse6. Here we use this system to show that regenerated heart muscle cells are derived from the proliferation of differentiated cardiomyocytes. Furthermore, we show that proliferating cardiomyocytes undergo limited dedifferentiation characterized by the disassembly of their sarcomeric structure, detachment from one another and the expression of regulators of cell-cycle progression. Specifically, we show that the gene product of polo-like kinase 1 (plk1) is an essential component of cardiomyocyte proliferation during heart regeneration. Our data provide the first direct evidence for the source of proliferating cardiomyocytes during zebrafish heart regeneration and indicate that stem or progenitor cells are not significantly involved in this process.

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Figure 1: Regenerated cardiomyocytes are derived from differentiated cardiomyocytes.
Figure 2: Differentiated cardiomyocytes re-enter the cell cycle.
Figure 3: Cardiomyocytes dedifferentiate, resulting in the disassembly of sarcomeric structure and detachment.
Figure 4: plk1 is necessary for cardiac regeneration.

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Acknowledgements

We thank M. C. Fabregat, C. Rodriguez Esteban and I. Dubova for technical assistance, and A. Faucherre for constructive criticism of the manuscript. E.S. was the recipient of a pre-doctoral fellowship from the Ministry of Innovation, Universities and Enterprise (DIUE), Generalitat de Catalunya. This work was supported by grants from Fundacion Cellex, the Ipsen Foundation, the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi-Aventis, the Ministry of Science and Innovation (MICINN), CIBER, and the National Institutes of Health.

Author Contributions C.J., A.R. and J.C.I.B. conceived the project and designed the experiments. C.J. performed the molecular biology and established the transgenic lines. C.J., E.S. and M.R. conducted the experiments. M.M. performed the immunohistochemistry and confocal/transmission electron microscopy imaging. C.J., A.R. and J.C.I.B. wrote the manuscript.

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Author notes

  1. Eduard Sleep, Marina Raya & Angel Raya

    Present address: Present addresses: Control of Stem Cell Potency group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 15, 08028 Barcelona, Spain (E.S., A.R.); Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), Dr Aiguader Street 88, 08003 Barcelona, Spain (M.R.).,

Authors and Affiliations

  1. Center of Regenerative Medicine in Barcelona,,

    Chris Jopling, Eduard Sleep, Marina Raya, Mercè Martí, Angel Raya & Juan Carlos Izpisúa Belmonte

  2. Networking Center of Biomedical Research in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Dr Aiguader Street 88, 08003 Barcelona, Spain ,

    Eduard Sleep, Angel Raya & Juan Carlos Izpisúa Belmonte

  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain ,

    Angel Raya

  4. Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ,

    Juan Carlos Izpisúa Belmonte

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  1. Chris Jopling
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Correspondence to Juan Carlos Izpisúa Belmonte.

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Jopling, C., Sleep, E., Raya, M. et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464, 606–609 (2010). https://doi.org/10.1038/nature08899

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