Community Research and Development Information Service - CORDIS

Final Report Summary - CARDIOGEN (The Molecular Mechanisms of Heart Regeneration)

The molecular mechanisms of heart regeneration
Heart disease has now become one of the most common causes of fatality. Indeed, many European countries report that heart disease is the number one cause of death and disability 1. Unlike adult mammals, zebrafish are capable of completely regenerating their heart after an extensive insult 2. The cellular source of the regenerated myocardium has been a controversial issue with a previous report suggesting that stem/progenitor cells are responsible for regenerating the missing tissue 3. In order to answer this question definitively, we developed the Cre/tamoxifen lineage tracing system widely utilised in mice but previously undescribed in zebrafish 4. This system allowed us to determine that the regenerated myocardium is in fact produced by the proliferation of existing cardiomyocytes 5,6. By adopting a similar experimental strategy to our approach in the zebrafish, Porrello et al found that neonatal mice also possess the ability to regenerate their heart via the proliferation of existing cardiomyocytes, indicating that mammals do have the potential for zebrafish-like heart regeneration 7. We are currently working to understand the molecular mechanisms of heart regeneration in zebrafish and hope this will provide a basis to one day induce heart regeneration in humans.

Results- Using transcriptomic data generated from regenerating zebrafish hearts we have been able to identify a number of genes and processes necessary for successful heart development and regeneration. We have generated a transgenic zebrafish line which conditionally expresses a dominant negative form of gene A. When we express this dominant negative gene during heart regeneration in zebrafish this process is severely disrupted indicating that this gene plays a critical role in successful heart regeneration. We have also recently determined that macrophages are essential for successful heart regeneration in zebrafish. We found that macrophages express a particular gene which is involved in breaking down the scar tissue associated with cardiac injury. By analyzing the macrophage response in adult mammals we hope to determine whether there are differences in the macrophage response and whether we can target this population of cells for cellular therapeutics. We are also assessing whether mechanosensory genes are involved in heart development/regeneration. Recently we have found that the gene Y is a functional mechanosensitive ion channel present in endothelial cells which responds to hemodynamic forces in the heart by triggering the release of nitric oxide in the outflow tract during cardiogenesis. We have also analysed exomic data from patients who suffer from bicuspid valve disease and found that deleterious mutations in this gene are associated with this condition.
Conclusions- We have identified a number of genes and processes that are required for successful heart regeneration in zebrafish. We are now in a position to translate these findings to mammals to determine whether these genes are able to induce regeneration in adult mammals and ultimately humans. Furthermore we have also identified a gene which is required for heart development in zebrafish. By analyzing human patients we have been able to determine that deleterious mutations in this gene are associated with bicuspid aortic valve disease, one of the most common congenital heart defects.
Impact- By identifying gene which are necessary for successful heart regeneration in zebrafish we are moving closer to being able to trigger a similar process in humans. Because adult humans cannot regenerate their heart any genes we identify in zebrafish may represent novel targets for inducing a similar regenerative response in adult humans following a myocardial infarction. By studying mutations that can lead to CHD will deepen our knowledge of normal and pathological tissue remodelling. This data could potentially be incorporated in clinical diagnostics allowing for rapid interventions, which will reduce infant morbidity and will allow us to identify new pathways as possible innovative therapeutic targets.

1 Allender, S., Scarborough, P., O'Flaherty, M. & Capewell, S. Patterns of coronary heart disease mortality over the 20th century in England and Wales: Possible plateaus in the rate of decline. BMC public health 8, 148 (2008).
2 Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science (New York, N.Y 298, 2188-2190 (2002).
3 Lepilina, A. et al. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127, 607-619 (2006).
4 Dor, Y., Brown, J., Martinez, O. I. & Melton, D. A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41-46 (2004).
5 Jopling, C. et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464, 606-609 (2010).
6 Kikuchi, K. et al. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 464, 601-605 (2010).
7 Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science (New York, N.Y 331, 1078-1080, doi:331/6020/1078 [pii]10.1126/science.1200708 (2011).

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