Study maps molecular mechanisms crucial for new approach to heart disease therapy

February 13, 2018, University of North Carolina Health Care
Study maps molecular mechanisms crucial for new approach to heart disease therapy
These cardiomyocytes (green with blue nuclei) had been fibroblasts before Frank Conlon's UNC lab reprogrammed them. Credit: Conlon Lab, UNC-Chapel Hill

Creating new healthy heart muscle cells within a patient's own ailing heart. This is how scientists hope to reverse heart disease one day. Today, a new study led by UNC-Chapel Hill researchers reveals key molecular details that should be useful in developing this ambitious approach.

In this study, published in Cell Reports, two labs at UNC and a group at Princeton University reprogrammed ordinary cells called fibroblasts into new and healthy , and recorded changes that appear to be necessary for this reprogramming.

"From these studies we may be able to define pathways to increase the efficiency of fibroblast reprogramming," said senior author Frank Conlon, PhD, professor of genetics in the UNC School of Medicine and professor of biology in the UNC College of Arts and Sciences.

Heart disease kills more than 600,000 people each year in the United States alone and remains the leading cause of death for both men and women. It typically arises from the narrowing or blockage of coronary arteries and involves the progressive replacement of heart muscle cells () with scar tissue - leading to a loss of heart function and ultimately heart failure.

This progressive disease process occurs in part because cardiomyocytes have a very limited ability to proliferate and replace damaged heart muscle. Scientists therefore have been experimenting with techniques to transform fibroblasts - collagen-making cells that are abundant in the - into new cardiomyocytes. They have shown that they can make this therapeutic cell-reprogramming process work in the diseased hearts of lab mice and thereby improve . But the process isn't as efficient as it needs to be for clinical use, and scientists are still learning why.

"The application of this technology has been limited by our lack of understanding of the molecular mechanisms driving this direct reprogramming process," said Conlon, who is also a member of the UNC McAllister Heart Institute.

For this study, Conlon's lab - in collaboration with the UNC McAllister Heart Institute lab of Li Qian, PhD, and the Princeton lab of Ileana Cristea, PhD - employed advanced techniques to map changes in protein levels in fibroblasts as they underwent reprogramming into cardiomyocytes.

First they triggered the reprogramming using a technique based on one Qian developed in 2012. They exposed fibroblasts to an engineered retrovirus that enters the cells and starts producing three key "transcription factor" proteins, which effectively reprogram gene expression in the cells, causing the cells to turn into cardiomyocytes within a few days.

The researchers examined the levels of thousands of distinct proteins in the during the three-day transformation from fibroblasts to cardiomyocytes. In so doing, said Conlon, "We revealed a carefully orchestrated series of molecular events."

The data suggest that the reprogramming process kicked off at about 48 hours after the viruses entered the and significantly affected the abundance of 23 classes of protein.

One of the most striking changes was a sharp rise in the level of a protein called Agrin, which has been found to promote repair processes in damaged hearts. Agrin also inhibits another signaling pathway called the Hippo pathway, known to be involved in regulating organ size. This finding - one of hundreds of individual clues generated by the study - raises the possibility that inhibition of Hippo signaling is needed for cardiomyocyte reprogramming.

Future studies will determine which of these myriad changes does indeed drive reprogramming, and more importantly which changes can be enhanced to improve reprogramming efficiency.

Explore further: Post-heart attack: How can scar tissue be turned back into healthy heart muscle?

Related Stories

Post-heart attack: How can scar tissue be turned back into healthy heart muscle?

September 26, 2017
Heart disease continues to be the leading cause of death worldwide, partly due to limited therapeutic options and the heart's inability to regenerate healthy cells called cardiomyocytes after heart attacks. Scientists at ...

Scientists describe the mechanism of heart regeneration in the zebrafish

February 12, 2018
Some animals, including the zebrafish, have a high capacity to regenerate tissues, allowing them to recovery fully after cardiac injury. During this process, the heart muscle cells divide to replace the damaged tissue. However, ...

How to turn damaged heart tissue back into healthy heart muscle—new details emerge

October 25, 2017
Reversing scar tissue after a heart attack to create healthy heart muscle: this would be a game-changer in the field of cardiology and regenerative medicine. In the lab, scientists have shown it's possible to change fibroblasts ...

How Gata4 helps mend a broken heart

August 15, 2017
During a heart attack, blood stops flowing into the heart; starved for oxygen, part of the heart muscle dies. The heart muscle does not regenerate; instead it replaces dead tissue with scars made of cells called fibroblasts ...

Cardiomyocytes fuse when the heart grows and regenerates

February 9, 2018
Cardiomyocytes fuse during cardiac development and regeneration. A scientist of the German Centre for Cardiovascular Research (DZHK) discovered these previously unknown processes with the aid of genetically modified zebrafish ...

Recommended for you

Study examines the rise of plaque in arteries

May 25, 2018
The accumulation of cholesterol plaques in artery walls can lead to atherosclerosis, or the hardening of arteries that contributes to heart attacks and strokes. In a new study, Yale researchers investigate how plaque cells ...

Low-dose aspirin could help pregnant women with high blood pressure avoid a dangerous condition

May 25, 2018
A daily dose of aspirin could help pregnant women in the first stage of high blood pressure avoid a condition that puts both mother and baby in danger, according to a new study.

Study shows in-home therapy effective for stroke rehabilitation

May 24, 2018
In-home rehabilitation, using a telehealth system and supervised by licensed occupational/physical therapists, is an effective means of improving arm motor status in stroke survivors, according to findings presented by University ...

Surgery involving ultrasound energy found to treat high blood pressure

May 23, 2018
An operation that targets the nerves connected to the kidney has been found to significantly reduce blood pressure in patients with hypertension, according to the results of a clinical trial led in the UK by Queen Mary University ...

New guidelines mean 1 in 3 adults may need blood pressure meds

May 23, 2018
(HealthDay)—One out of every three U.S. adults has high blood pressure that should be treated with medication, under guidelines recently adopted by the two leading heart health associations.

To have or not to have... your left atrial appendage closed

May 22, 2018
Each year in the U.S., more than 300,000 people have heart surgery. To reduce risk of stroke for their patients, surgeons often will close the left atrial appendage, which is a small sac in the left side of the heart where ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.