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Notch signalling in zebrafish heart regeneration

Heart failure is one of the major causes of mortality worldwide. After myocardial infarctions the human cardiomyocytes are incapable of proliferating to give rise to new cardiac muscle and, instead, non-contractile scar tissue is formed. On the other hand, vertebrates as zebrafish can fully regenerate their heart after amputation, cryoinjury or genetic ablation of cardiomyocytes. Also, 1-day old mice can regenerate their hearts after amputation, ability that is lost around one week after birth. Importantly, although the adult mammalian heart does not regenerate a low rate of cardiomyocyte proliferation has been recently reported. Therefore, these examples provide hope that science can find the way to enhance the very poor regenerative abilities of the human heart.

A first step is to fully understand how zebrafish, for example, regenerate their hearts. Now a recent paper from the laboratory of Geoffrey and Caroline Burns reports on the function of Notch signalling during zebrafish heart regeneration (http://www.ncbi.nlm.nih.gov/pubmed/24474765). Previous reports had indicated that some components of the Notch signalling were upregulated after heart amputation, however the functional relevance of such upregulation remained to be determined. In this paper the authors show first how of the four zebrafish Notch receptors, notch1a, notch1b and notch2 were upregulated in the endocardium after amputation, especially in regions close to the wounds. On the other hand, notch1a and notch2 were also upregulated in the epicardium covering the wound. Finally, no expression of any notch receptor was detected in the myocardium in un-injured and injured hearts.

Because of a possible redundancy of the several notch genes, the authors used a dominant negative isoform of the MAML protein, a pan-Notch pathway inhibitor, under the control of a heat shock promoter. After amputation the animals were heat shocked daily for 30 days and then they checked the amount of regeneration. Notch inhibition resulted in failed myocardium regeneration and instead a fibrotic scar was seen at the site of amputation. Because notch genes were upregulated in the endocardium and epicardium the authors analysed then what happened to those tissues after Notch inhibition. Remarkably, the silencing of this pathway did not affect the normal response of these tissues to amputation. Thus, in normal conditions, after amputation epicardial cells go through an epithelial-to-mesenchymal transition to produce epicardial derived cells (EPDCs) that at the end become smooth muscle cells that support the regenerating coronary network. This activating response to form EPDCs was normally observed after Notch inhibition. On the other hand, after amputation endocardial cells upregulate the expression of raldh2 and shift from flattened to rounded morphology. This change in the morphology persists at the wound site several days after amputation. Animals in which the Notch pathway had been silenced showed a normal activation of the endocardium after amputation.

Also, although the treated animals lacked regenerated myocardium they had endothelial tubes in the wound area suggesting that Notch signalling seemed dispensable for initiating coronary artery regeneration. In contrast when they checked what happened to the myocardium after amputation the authors found out that whereas the cardiomyocyte dedifferentiation process triggered by the amputation was not affected in a Notch signalling-inhibited background, their proliferation was severely impaired. These results suggest that Notch signalling would be required for cardiomyocytes proliferation.

The authors wanted then to check whether overactivating Notch signalling could have a beneficial effect on heart regeneration. Surprisingly, however, they found that the hyperactivation of Notch signalling resulted in collagen deposition at the wound region and a significant decrease of cardiomyocyte proliferation. These results indicate that cardiomyocyte proliferation would depend on the fine regulation of the Notch signalling. In fact such fine regulation of this pathway has been also proposed during zebrafish fin regeneration in which, again, both inhibition and overactivation of Notch signalling impairs regeneration (although by affecting either proliferation or differentiation).

In parallel to the characterization of the Notch pathway during heart regeneration the authors describe also in this paper that the new coronary endothelium derives, at least partially, from pre-existing endothelium. This agrees with previous observations in fish as well as in salamanders in which new cell types during regeneration appear to derive from the same pre-existing cell types.

In summary this paper shows how Notch signalling is activated in the endocardium and epicardium upon ventricular apex amputation. Remarkably, its silencing does not affect endocardium and epicardium activation but blocks regeneration by impairing cardiomyocyte proliferation in a non-cell autonomous manner. Further experiments should help to better understand how overactivating Notch signalling inhibits also cardiomyocyte proliferation in the zebrafish heart.

 

 

 

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Francesc Cebrià

Francesc Cebrià

Francesc Cebrià

I am a Biologist and Professor at the University of Barcelona. I do my research on a fascinating animal: freshwater planarians. You can cut them in as many pieces as you want and each piece will regenerate a complete new flatworm in very few days. In this blog I will keep you updated on the latest news on the field of animal regeneration. You will be able to follow the latest research on how planarians, axolotls, newts, cnidarians and other animals are able to regenerate parts of their bodies

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