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Transdifferentiation during zebrafish heart regeneration

Because of the high incidence of deaths and diseases related to heart failure may research is being done to try to promote the differentiation of new cardiomyocytes in the human heart. However, and as it happens for many other vital organs, humans are quite bad regenerators.  However, at foetal stages mammals conserve some degree of heart regeneration. In fact, newborn mice are able to regenerate their heart if a part of it gets amputated during the first week. After that initial period the capacity of heart regeneration gets lost. Other vertebrates, such as zebrafish are able to regenerate their hearts as adults. In those animals what it has been reported is that upon amputation cardiomyocytes are able to dedifferentiate into a proliferative stage, divide and re-differentiate again into new cardiomyocytes.

A recent paper from the laboratory of Neil C. Chi has reported that in zebrafish embryos atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to successful heart regeneration (http://www.ncbi.nlm.nih.gov/pubmed/23783515). Specifically, the authors addressed the role of atrial cardiomyocytes that has been shown to divide in adult vertebrate hearts after a ventricular injury. The authors used a series of fluorescence reporter transgenes to distinctively label atrial and ventricular cardiomyocytes as well as a specific cell-ablation system to ablate ventricular cardiomyocytes from zebrafish embryos and follow their regeneration.

By doing it, the authors described how after cell ablation, pre-existing atrial cardiomyocytes migrate to the ventricle and transdifferentiate into ventricular cardiomyocytes. Along this pathway atrial cardiomyocytes appear to go through an intermediate progenitor-like stage. In addition to characterizing this transdifferentiation event at the molecular (gene expression) level the authors also reported that electrophysiological recordings showed how the newly transdifferentiated ventricular cardiomyocytes exhibited electrical features similar to endogenous ventricular cardiomyocytes (and distinct to those from atrial cardiomyocytes).

It has been previously suggested that endocardial activation is required for heart regeneration. Here, the authors showed how Notch signalling is activated in atrial endocardial cells upon ventricular ablation. However, no evidence of reprogramming of those endocardial cells into cardiomyocytes was observed.  Remarkably, DAPT-mediated inhibition of Notch signalling resulted in impaired ventricular regeneration with a reduced migration of atrial cardiomyocytes into the injured ventricle. Thus, these results open the possibility that Notch signalling may be required to regulate heart regeneration through a non-cell autonomous mechanism.

In summary, this paper shows how a ventricular injury is able to induce in vivo the reprogramming of atrial cardiomyocytes into a progenitor-like stage from which ventricular cardiomyocytes differentiate. One of the issues to analyse in the future is whether these transdifferentiation potential is age-dependent because when ventricular ablations were done in adult zebrafish the authors found a decrease in the number of transdifferentiated atrial cardiomyocytes that contribute to ventricular regeneration. Also, future analyses should determine whether atrial cells in mammals retain this transdifferentiation potential to provide a cellular source during repair and regeneration.

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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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