A Canadian study has found the mechanism underlying regeneration of damaged heart tissue in zebrafish, with researchers optimistic that the findings may give rise to heart regeneration therapeutics for human use.
“This discovery will make it possible to study the potential of this molecule for treatment purposes in people with heart damage,” one of the authors of the study, Prof. Ruben Juez of Université de Montréal, said in the university’s media release.
While zebrafish are able to regenerate and repair their heart tissue and blood vessels after an injury through a heart attack, humans cannot. Hence, heart attacks can easily lead to impaired heart function and death.
Therefore, researchers believe that by understanding the molecules activated in zebrafish and then administering the same molecules as a therapeutic, repair could also be a possibility for humans.
“We already knew that, after cardiac injury, vascular endothelial growth factor C (Vegf-C) was upregulated in adult zebrafish, and that this factor was involved in cardiac regeneration,” said Juez.
The study conducted by an international research team found that following a cardiac injury in zebrafish, cells that line blood vessels will regenerate and upregulate the gene Vegf-C. This gene will then activate a gene called Emilin2a, which will produce the Emilin2a protein and activate a gene called Cxcl8a.
Cxcl8a found in the heart cells will then commence repair of damaged heart cells as well as growth of damaged coronary blood vessels [blood vessels that supply the heart] to return cardiac function, the study finds.
Further, the researchers found that although Vegf-C was the most upstream in the pathway for the series of regenerations, the gene does not need to be activated for heart regeneration.
Simply by manipulating the Emilin2a protein produced by the Emilin2a gene, researchers found they were able to “modulate the regenerative response of cardiac muscle cells” through Cxcl8a.
The researchers identified Emilin2a and Cxcl8a through a series of elimination and found inhibiting Vegf-C caused scarring and reduced regeneration of heart vessels and tissues, confirming Vegf-C as an essential gene for heart regeneration.
The researchers then examined which gene was also inhibited when Vegf-C was suppressed, thereby identifying Emilin2a and Cxcl8a, which were further downstream in the pathway.
Since the process of regeneration does not occur in human heart cells, the tissues that are damaged in the heart attack [commonly caused by a blockage in the heart vessels] will usually die, forming a scar with the heart’s cardiac output [heart rate and blood volume pumped] reduced.
If the tissue damaged is in a non-essential area of cardiac function, then the person may live; but if the tissue damage occurred in a critical area, then the person will likely die.
However, researchers believe there is hope for regeneration. Previous mice studies on adult mice that are no longer able to regenerate their heart found that a certain level of reparation took place after injections with the Vegf-C.
The researchers of that study found that mice that suffered a heart attack saw improvement in cardiac output and performance after an injection of Vegf-C through the abdomen.
The findings suggested that similar methods may be applicable to humans, and if the Vegf-C proteins do not work, the recent study also found the alternative of using Emilin2a protein, which may be effective as a therapeutic.
“These studies aid in understanding the mechanisms underlying coronary revascularization [reformation of blood vessels in the heart] in zebrafish, with potential therapeutic implications to enhance revascularization and regeneration in injured human hearts,” the authors wrote in the study. The results have been published in the journal Circulation Research.