Regenerating broken hearts

Chris Jopling joined the CMRB as a postdoctoral research scientist in June 2007. Since then, he has been investigating heart regeneration in zebrafish. The technicians M. Carme Fabregat and Guillermo Suñé, as well as Veronika Sander, another postdoctoral researcher, collaborate with the English biochemist in this line of research.

They are all trying to find out which genes are involved in heart regeneration in the zebrafish, Danio rerio. “You can cut off up to 20% of a ventricle of an adult fish, and in one month it is completely regenerated”, explains Jopling. Mammals are able to regenerate some tissues, such as blood or liver, but not heart. At least that is what scientists used to think. Earlier this year, it was found that newborn mice were able to regenerate their hearts, even though this ability was lost after just one week. This means that mammals actually do have the potential for heart regeneration.

Not everything is stem cells

For years, researchers have thought that stem cells were responsible for regeneration in the heart, and many groups around the world look for these stem cells. But Jopling and his colleagues at the CMRB showed, in 2010, that heart regeneration in zebrafish did not involve stem cells at all (you can see here the full paper). Rather, it was the cardiomyocytes (heart muscle cells) that dedifferentiated and started proliferating upon heart amputation. “Interestingly, the neonate mice regenerated their heart in the same way that the zebrafish do, that is, through the differentiated heart cells, and not through stem cells”, says Sander.

So far, only five genes have been demonstrated to be directly involved in heart regeneration in zebrafish. The aquatic animals group has identified three more genes that, if mutated or over-activated, block regeneration. In order to find these genes, the researchers followed a specific protocol. “We make a small cut on the ‘chest’ of the fish (just above its heart). If you then squeeze gently, the heart ventricle comes out. You then just grab it with very small forceps and make a cut with the scissors”, explains Jopling. The fish are sent back to their tank, where they continue swimming peacefully. Fourteen and thirty days after the amputation, the researchers check the status of heart regeneration. At the first time point, normal fish are in the peak of proliferation and, after a month, regeneration is complete. When the fish are transgenic or exposed to chemical additives that inhibit genes involved in regeneration, the process is halted.

A long way to go to mend a broken heart

The final aim of the research is to regenerate a human heart after a stroke. But there is still a long way to go. The CMRB group has already planned their next steps. First, they will check how the newly identified genes affect the expression of other genes by using microarrays and comparing the gene expression of a normal regenerating heart with that of a heart in which these genes have been modified. That should help to better understand how these genes regulate regeneration and which pathways they are involved in.

The scientists will then move on to mice. Since most genes in the zebrafish have homologues in mammals, they will check whether the identified genes are able to induce proliferation of cultured mouse cardiomyocytes. Mouse heart muscle cells usually don’t proliferate, so a cell culture can only last about a week. If the researchers are able to get the cells in the culture to replicate and proliferate by using these new genes, they will then generate transgenic mice. And bring us all a step closer to mending a broken heart.

This article was published in the El·lipse publication of the PRBB.


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