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Zebrafish Study Sheds Light on Self-Healing Heart Regeneration Mechanism

Zebrafish heart cells under the microscope, 60 days after injury, showing their structure has completely regenerated.
Zebrafish heart 60 days after injury showing the structure of the heart muscle cells have completely regenerated. Credit: Phong Nguyen/Hubrecht Institute.
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Researchers from the Hubrecht Institute have identified a new self-healing heart regeneration mechanism in zebrafish with the potential to contribute toward new human cardiovascular disease treatments. The research is published in Science.

Mending a broken heart

Cardiovascular diseases are a leading cause of death worldwide – an estimated 17.9 million people die from cardiovascular diseases every year.

Many of these deaths are related to heart attacks, also known as myocardial infarctions. During a heart attack, blood clots can block the vessels that supply the heart with oxygen and nutrients and prevent them from reaching the heart tissue. The obstructed heart muscle cells begin to die, and due to their limited self-healing capacity, this can eventually lead to heart failure.

Although therapies exist that manage the symptoms of heart failure, there are no curative treatments that can replace the lost tissue with functional, mature heart muscle cells.

However, some animals have an incredible capacity to recover from heart damage. Zebrafish – a species of freshwater fish native to south Asia – are one such animal. They can fully recover cardiac function within 90 days of experiencing heart damage as any surviving muscle cells can divide to replace damaged and dying cells.

Previous studies have identified some factors capable of stimulating heart muscle cells to divide, though the fate of these newly formed cells had not been well understood. Therefore, the researchers in the current study aimed to investigate how zebrafish achieve their regenerative success.

“It is unclear how these cells stop dividing and mature enough so that [they can] contribute to normal heart function,” said Dr. Phong Nguyen, postdoctoral researcher and lead author of the study. “We were puzzled by the fact that in zebrafish hearts, the newly formed tissue naturally matured and integrated into the existing heart tissue without any problems.”

Boosting heart cell maturation

First, the researchers developed a technique that allowed them to study how the newly formed zebrafish heart cells matured in detail. They were able to grow and culture slices of injured zebrafish hearts in the laboratory which they examined using live cell imaging. They focused on the movement of calcium ions in and out of the heart muscle cells as this is important for controlling the heartbeat and can also be used to predict the cells’ maturity.

The live cell imaging revealed after the heart muscle cells divide, calcium movements also changed over time. “The calcium movement in the newly divided cell was initially very similar to embryonic heart muscle cells, but over time the heart muscle cells assumed a mature type of calcium movement,” said Nguyen. “We found that the cardiac dyad, a structure that helped to move calcium within the heart muscle cell, and specifically one of its components, LRRC10, was crucial in deciding whether heart muscle cells divide or progress through maturation. Heart muscle cells that lack LRRC10 continued to divide and remained immature.”

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With LRRC10 established as an important factor involved in cell division and maturation of zebrafish heart muscle cells, Nguyen and colleagues wanted to determine whether the same could also be true in mammalian cells.

Mouse models and lab-grown human heart muscle cells were engineered to produce LRRC10, which produced changes similar to those observed in the zebrafish hearts – calcium transport was altered, cell division reduced and cell maturation increased.

“It was exciting to see that the lessons learned from the zebrafish were translatable as this opens new possibilities for the use of LRRC10 in the context of new therapies for patients,” added Nguyen.

Promise for cardiovascular disease therapies

Overall, the study suggests that LRRC10 has the potential to boost heart muscle cell maturation through changes in calcium handling. This could aid the development of therapies that aim to transplant lab-grown cells into damaged hearts, as although these therapies hold great promise, immature lab-grown cells fail to communicate properly with the rest of the heart and can lead to arrhythmias.

“Although more research is needed to precisely define how mature these lab-grown heart muscle cells are when treated with LRRC10, it is possible that the increase in maturation will improve their integration after transplantation,” said Professor Jeroen Bakkers, senior author of the study. “Additionally, current models for cardiac diseases are frequently based on immature lab-grown heart muscle cells. Ninety percent of promising drug candidates found in the lab fail to make it to the clinic and the immaturity of these cells could be one contributing factor [to] this low success rate. Our results indicate LRRC10 could improve the relevance of these models as well”.

Reference: Nguyen PD, Gooijers I, Campostrini G, et al. Interplay between calcium and sarcomeres directs cardiomyocyte maturation during regeneration. Science. 2023;380(6646):758-764. doi: 10.1126/science.abo6718

This article is a rework of a press release issued by the Hubrecht Institute. Material has been edited for length and content.