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Advances in heart regeneration, thanks to the zebrafish

New research on the regenerative abilities of the zebrafish shed light on the properties of the epicardium, and could help to provide a new treatment for humans with heart conditions, according to a study published recently in Nature.1

The study found that when this critical layer of the heart is damaged, the whole repair process is delayed as the epicardium undergoes a round of self-healing before tending to the rest of the heart. The new research showed that the process requires signaling through a protein called sonic hedgehog, and demonstrated that adding this molecule to the surface of the heart can drive the epicardial response to injury.

The finding points to a possible target for repairing the damage caused by a heart attack. Senior author Professor Kenneth D Poss (Duke University School of Medicine) said: “The best way to understand how an organ regenerates is to deconstruct it. So for the heart, the muscle usually gets all the attention because it seems to do all the work…But we also need to look at the other components and study how they respond to injury. Clearly, there is something special about the epicardium in zebrafish that makes it possible for them to regenerate so easily.”

Professor Poss has been studying heart regeneration in zebrafish for the last 13 years. As a postdoctoral fellow he was the first to show that the puny, striped fish could regrow severed pieces of heart tissue. Since then, his group has found that this regeneration involves the input of the epicardium, a thin layer of cells that cover the surface of the heart.

“The epicardium is underappreciated, but we think it is important because similar tissues wrap up most of our organs and line our organ cavities,” Professor Poss said. “Some people think of it as a stem cell because it can make more of its own, and can contribute all different cell types and factors when there is an injury. The truth is we know surprisingly little about this single layer of cells or how it works. It is a mystery.”

In this study, postdoctoral fellow Jinhu Wang performed open-heart surgery on live zebrafish, removing approximately one fifth of the vital organ. Afterwards he used a set of sophisticated genetic tools to kill 90% of the epicardial cells and then measured how well the heart healed at various time points. He found that removing this outer layer created a clear lag in regeneration, but that eventually the healing process caught up to that of zebrafish with an intact epicardium.

The results suggested that the 10% of epicardial cells left behind were able to rebuild the epicardial layer before moving on to heart muscle. Intrigued by the finding, Poss decided to focus the next series of experiments on the epicardium and its ability to regenerate itself. Jingli Cao, another postdoctoral fellow in his laboratory, figured out a way to remove hearts from zebrafish and grow them in dishes in the laboratory, where the tiny two-chambered organs continued to beat and behave as if they were still tucked inside the organism.

As they had before, the researchers destroyed most of the heart’s epicardial layer, but this time they put the “explanted” organs under the microscope every day to capture the regeneration in action. They showed that the epicardium regenerated rapidly, covering the heart like a wave from the base of one chamber to the tip of the other in just a week or two.

The researchers then used this model to search for small molecule compounds or drugs that would affect the ability to regenerate. They screened molecules known to be involved in development of embryos, like fibroblast growth factors and sonic hedgehog, and found that the latter was critical for the regeneration process. The researchers now plan to perform larger screens for molecules that could enhance heart repair in zebrafish, and perhaps one day provide a new treatment for humans with heart conditions.

Speaking to BJC Arrhythmia Watch, Professor Poss said: “The epicardial layer of the heart is an important cell type for the process of cardiac muscle regeneration, ostensibly by improving vascularisation, releasing cardiac muscle cell mitogens, and acting as a scaffold…the epicardium itself has particularly high regenerative potential, and regenerates in a stereotypic manner directed by the neighbouring cardiac outflow tract and involving secreted signalling proteins called Hedgehog factors.”

“As far as clinical applications, the epicardium is a dynamic, injury-responsive tissue – once underappreciated but now directly under the lens of many cardiac disease researchers.  Our study reveals key influences behind its dynamic properties, and suggests that the responsiveness and proliferative capacity of epicardium can be harnessed to improve heart regeneration in mammals, including humans.  Although achieving heart regeneration in humans has been a major clinical goal for a decade, this is still no effective therapy.  I strongly feel that there is still much discovery research to do to fully understand how and why heart regeneration happens, and that findings such as ours from models like zebrafish provide a highly informative blueprint for potential regenerative therapies of the human heart,” Professor Poss concluded.

References

1. Wang J, Cao J, Dickson AL, Poss KD. Epicardial regeneration is guided by cardiac outflow tract and Hh signalling. Nature 2015. http://dx.doi.org/10.1038/nature14325

Published on: May 28, 2015

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