Using Zebrafish Models to Study Cardiovascular Disease

Maryline-squareprofile.jpgMaryline Abrial, PhD, is a postdoctoral research fellow in the Burns Lab at the Cardiovascular Research Center at Massachusetts General Hospital. She took part in a science communication internship at the Mass General Research Institute this fall. She wrote this first-person account of her life as a researcher as part of her internship.

Background and Education

I think what drew me to the biological sciences was a passionate high school biology teacher, who was great mentor and advisor over the years of my undergraduate and graduate training.

I have always found biological processes fascinating. The complexity of them can be very challenging, but understanding and deciphering even a small part feels very rewarding when you can impact human diseases.

Since I started my graduate studies in France in University Claude Bernard in Lyon, I have focused on cardiovascular science. During my PhD, I studied myocardial infarction, which is more commonly known as a heart attack.

My work focused on understanding cellular interactions and especially how non-contractile cell types can help to protect the cells in charge of contraction after an injury such as a heart attack.

After my PhD, I decided to pursue my work in the field of cardiovascular sciences in the exciting scientific environment that Boston offers. I joined the laboratory of Dr. Caroline Burns and Dr. Geoffrey Burns in the Cardiovascular Research Center at Massachusetts General Hospital.

The zebrafish as a model organism

The Burns laboratory studies heart development and regeneration in a particular animal model—the zebrafish.

Unlike humans, zebrafish can regenerate new cardiac tissue after an injury such as a heart attack, which makes them a great model to study the cellular and molecular mechanisms involved in cardiac regeneration.

The zebrafish is also a powerful vertebrate model to study cardiovascular developmental biology because of its rapid external development, the large number of eggs that can be obtained and, more importantly, its beating developing heart that can be observed only 24 hours after fertilization of the egg.

While the zebrafish heart, which is comprised of a single ventricle and atria, is a simpler version of the human heart, the mechanisms regulating its development share much in common.

Investigating aortic arch development

After joining the Burns lab, I slowly became familiarized with zebrafish, and all the genetic tools and imaging techniques that make them such an attractive research model.

I worked closely with a senior research fellow who was studying the development of the great arteries of the heart (also named Pharyngeal Arch Arteries, or PAAs) during embryonic development.

In humans, the PAAs start off symetrically, but then undergo intensive remodeling before taking their final asymetrical shape. Impaired remodeling of those PAAs during development can lead to congenital heart diseases such as Tetralogy of Fallot.

This remodeling process is similar throughout vertebrates, and the zebrafish is a great model organism to visualize and study the cellular progenitors that give rise to these specific arteries.

Using the zebrafish to perform small molecule screening, we uncovered a specific signaling pathway that is involved in the differentiation of great arteries’ cellular progenitors. Using genome-editing technologies, we engineered zebrafish lacking the function of two genes that are involved in this pathway.

Surprisingly, we found that those zebrafish embryos presented a phenotype similar to a human disease called Marfan Syndrome (MFS), a genetic disorder that affects the connective tissue.

People affected by MFS present symptoms in different parts of their bodies, but the most severe ones are linked to the cardiovascular system and include widening or aneurysm of the basis of the aorta (aortic root), which is the main artery carrying blood away from the heart.

This aneurysm can cause a dissection or a tear in the vessel, which will weaken it over time and could lead to a life threatening rupture.

We found that our zebrafish models, when engineered to lack the expression of these two genes, rapidly exhibit an impressive aortic aneurysm (in only 5 days) in a location that is anatomically equivalent to where human aortas are susceptible to developing aneurysm in MFS.

We have analyzed these zebrafish aneurysms and found several molecular hallmarks of the human disease, suggesting that the mechanisms by which zebrafish embryos develop aortic aneurysms are similar to those in Marfan patients.

The Marfan Foundation has funded my research for two years beginning in July of 2016. We are using zebrafish models in combination with genetic tools and microscopic imaging to complement ongoing work in the aneurysm field.

Although tremendous progress has been made in the past decade in the aneurysm research, several questions remain unknown regarding the drivers of the disease.

Current preventive medical therapies for Marfan patients are mainly aimed to reduce blood pressure to decrease the risk of life-threatening complications or to undergo cardiac surgery to repair the aortic root. But so far no therapy has been discovered that prevents or reverses the process of aortic dilation itself.

Because zebrafish embryos are so small and readily available, we can screen large collections of small molecules to looks for candidates that will prevent or cure aortic aneurysm in zebrafish.

In the long run, we hope that any small molecule that suppresses zebrafish aneurysm could be therefore tested in other laboratory models and eventually in humans to learn if they will prevent and/or reverse Marfan Syndrome-associated aneurysm.

The zebrafish gives us a tremendous advantage in studying the pathophysiology of cardiovascular diseases. With the progress of genome editing technologies now readily available, this model can be used to study specific cardiovascular diseases and help to further validate and understand the function of candidate genes identified in human cohorts affected by cardiovascular diseases.

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