Researchers Unveil Mechanism for Heart Regeneration, Paving the Way for Treating Cardiovascular Diseases
Scientists have made a significant breakthrough in understanding the regenerative process of the heart by studying zebrafish. This research has revealed a mechanism involving LRRC10 that promotes the maturation of heart muscle cells during the regeneration process. Remarkably, this mechanism has shown promising results when applied to human cells, potentially revolutionizing cardiovascular disease treatments and offering hope for the replacement of lost heart tissue.
Cardiovascular diseases, including heart attacks, are a leading cause of death worldwide due to the limited self-healing ability of the human heart. In contrast, zebrafish possess an extraordinary ability to recover from heart injuries. Building on this natural regenerative capacity, a team led by Jeroen Bakkers from the Hubrecht Institute embarked on uncovering the secrets behind zebrafish heart regeneration. Their investigation led to the discovery of a novel mechanism that triggers the maturation of heart muscle cells during the regenerative process. Notably, this mechanism exhibited a similar effect on mouse and human heart muscle cells, indicating an evolutionarily conserved process.
The findings of this study, published in Science on May 18th, hold immense potential for the development of new therapies targeting cardiovascular diseases. With an estimated 18 million deaths attributed to these conditions annually, heart attacks represent a significant portion of these fatalities. During a heart attack, a blood clot obstructs the supply of nutrients and oxygen to parts of the heart, resulting in the death of heart muscle cells and eventual heart failure.
Although existing therapies can manage symptoms, there is currently no treatment capable of replacing lost heart tissue with functional, mature heart muscle cells to cure patients. Zebrafish, on the other hand, provide a valuable role model as they can fully restore their cardiac function within 90 days after sustaining damage. The surviving heart muscle cells in zebrafish can divide and generate more cells, serving as a source of new tissue to replace the lost heart muscle cells. While previous studies have identified factors that stimulate heart muscle cell division, the maturation process of these cells has remained poorly understood.
To investigate the maturation process of newly formed tissue, the researchers developed a technique involving culturing thick slices of injured zebrafish hearts outside the body. This allowed them to observe the movement of calcium within heart muscle cells through live imaging. Calcium regulation plays a crucial role in controlling heart contractions and serves as an indicator of cell maturity. The study revealed that after heart muscle cells divide, their calcium movements change over time.
Phong Nguyen, the study’s first author, explains, “Initially, the calcium movement in the newly divided cells resembled that of embryonic heart muscle cells. However, over time, these cells adopted a mature type of calcium movement. We discovered that a structure called the cardiac dyad, which facilitates calcium movement within heart muscle cells, particularly a component known as LRRC10, played a vital role in determining whether heart muscle cells divide or mature. Heart muscle cells lacking LRRC10 continued to divide and remained immature.”
After establishing the significance of LRRC10 in ceasing cell division and initiating the maturation of zebrafish heart muscle cells, Nguyen and his colleagues tested the translatability of their findings to mammals. They induced the expression of LRRC10 in mouse and lab-grown human heart muscle cells and observed that LRRC10 altered calcium handling, reduced cell division, and promoted cell maturation in a manner similar to zebrafish hearts.
Excitingly, the lessons learned from zebrafish can potentially open up new therapeutic possibilities for patients. The study’s results highlight LRRC10’s potential to drive the maturation of heart muscle cells by regulating their calcium handling. This finding may aid scientists in addressing the lack of regenerative capacity in the mammalian heart by transplanting lab-grown heart muscle cells into damaged hearts.
While the therapy shows promise, the study revealed that these lab-grown cells are still immature and struggle to communicate effectively with the rest of the heart, leading to abnormal contractions known as arrhythmias.
Jeroen Bakkers, the last author of the study, notes, “Further research is needed to determine the maturity level of these lab-grown heart muscle cells when treated with LRRC10. However, it is possible that enhanced maturation will improve their integration after transplantation.” Bakkers also suggests that the immaturity of lab-grown heart muscle cells could be a contributing factor to the low success rate of drug candidates in the lab, indicating that LRRC10 has the potential to enhance the relevance of these models.
LRRC10 could play a significant role in generating lab-grown heart muscle cells that more accurately resemble a typical adult human heart. This development would greatly improve the chances of successfully developing new treatments for cardiovascular diseases. The study was a collaboration between the Hubrecht Institute, LUMC, AMC, UMC Utrecht, and Weizmann Institute and received funding from various organizations, including the Dutch Heart Foundation, Dutch CardioVascular Alliance, and Stichting Hartekind.
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Frequently Asked Questions (FAQs) about heart regeneration
What is the key mechanism behind heart regeneration?
Researchers have discovered a mechanism involving LRRC10 in zebrafish that promotes the maturation of heart muscle cells during the regeneration process. This mechanism triggers the transition of newly formed cells into mature heart muscle cells, aiding in the regeneration of the damaged heart tissue.
Can this mechanism be applied to human cells?
Yes, the mechanism discovered in zebrafish has shown promising results when applied to human heart muscle cells. The similar effect observed in mouse and human cells suggests an evolutionarily conserved process, offering potential for new treatments against cardiovascular diseases in humans.
What are the implications for cardiovascular disease treatments?
The findings provide insights into the development of new therapies for cardiovascular diseases. By understanding the mechanism behind heart regeneration, researchers can explore ways to stimulate the maturation of heart muscle cells and potentially replace lost heart tissue, improving treatment options for patients with cardiovascular conditions.
How does this research benefit current cardiac disease models?
Current models for cardiac diseases often rely on immature lab-grown heart muscle cells. The discovery of LRRC10’s role in promoting maturation could improve the relevance and accuracy of these models. This advancement may enhance the success rate of drug candidates and facilitate better understanding and treatment of cardiac diseases.
Is further research required?
Yes, further research is necessary to fully understand the maturation process of lab-grown heart muscle cells treated with LRRC10 and to assess the integration of these cells after transplantation. Continued investigations will help refine and optimize the application of this mechanism in developing successful therapies for cardiovascular diseases.
More about heart regeneration
- Science: Interplay between calcium and sarcomeres directs cardiomyocyte maturation during regeneration
- Hubrecht Institute
- Dutch Heart Foundation
- Dutch CardioVascular Alliance
- Stichting Hartekind
- European Molecular Biology Organization
- Human Frontier Science Program
- NWO-ZonMW Veni grant
- Horizon 2020 Framework Programme
- Netherlands Organ-on-Chip Initiative
- European Research Council
- Novo Nordisk Foundation Center for Stem Cell Medicine
- Netherlands Cardiovascular Research Initiative
