About injured hearts that grow back – Heart regeneration mechanism in zebrafish revealed

Zebrafish have a wonderful characteristic trait: they have extraordinary regenerative powers that go beyond the ability to regrow injured extremities. Even heart injuries heal up completely in this fish species. For cardiologists, who regularly treat heart attack patients, this would be a dream come true. Scientists at Utrecht University and Ulm University now have unravelled a central molecular mechanism that coordinates this healing process.

‘The injured tissue regenerates via the proliferation of heart muscle cells located near the wound border,’ Professor Gilbert Weidinger from the Institute for Biochemistry and Molecular Biology at Ulm University explains. The international research team – a collaboration between Weidinger’s lab and scientists at the Utrecht University Hospital – was able to show that the cell proliferation is regulated by a particular family of proteins: the so-called bone morphogenetic proteins (BMPs).

BMPs are signalling proteins that play an important role in cell-to-cell communication. The researchers were able to demonstrate that BMPs are activated particularly along the border between healthy and injured tissue.

The molecular biologists developed a special method for RNA sequencing (tomo seq) which allows them to locate the activity of various genes in the wound area and the adjacent tissue. ‘This generates a genome-wide atlas of gene expression and activity patterns, showing significant regional differences. This sheds light on which genes and cell signals are active in a regenerating heart both in the healthy and the injured tissue, or rather exactly along the border of the wound,’ says Chi-Chung Wu.

The PhD student from Hong Kong conducts research at Ulm University. Together with his colleague from Utrecht, Fabian Kruse, he is first author of the study, which has been published in the renowned journal Developmental Cell (2016/36: 36–49).

Using this sequencing technique, the scientists found that BMP signalling is activated by heart muscle cells in the wound border zone where healthy and injured tissue come together. With the help of transgenic zebrafish in which the BMP signalling pathway was either inhibited or amplified, the researchers were able to selectively influence the regeneration process. In the genetically modified animals where the BMP signalling pathway had been blocked, heart muscle cell proliferation was reduced considerably. In those animals with overly active BMP the regeneration was actually enhanced.

‘Surprisingly, this signalling pathway plays no role in cell division during embryonic heart development, only in heart regeneration due to injury,’ the scientists say in astonishment. This means that the tissue formation in the fish heart during embryonic development and during regeneration is regulated by two different processes.

There is another finding that astounds the researchers: ‘The BMP signalling is also active in the injured hearts of mice, but there the heart cells react in a dramatically different way: they die. Here the BMP doesn’t promote healing but causes the damaged cells to commit suicide,’ says Professor Jeroen Bakkers from Hubrecht Institute at the Utrecht University Hospital. He is, like Prof. Weidinger, co-corresponding author of this study.

The scientists now want to work out why heart cells in zebrafish and in mammals like mice react so differently, and which processes are ultimately responsible.

If mammals – which humans are classified as taxonomically – were able to replace injured heart cells in the same way as zebrafish there would be new hope for heart attack patients. The reason why a myocardial infarction, as this life-threatening event is also called, is so dangerous for humans is because the dying heart muscle cells cannot be replaced. This leads to extensive scarring of the heart muscle and causes the organ to lose strength. The medical relevance of this project is therefore tremendous. ‘Maybe one day it will be possible to considerably improve the regenerative capacity of human heart tissue with medication or therapies that have been developed on the basis of such fundamental research findings,’ the researchers hope.

Further information:
Prof. Dr. Gilbert Weidinger; Email: gilbert.weidinger@uni-ulm.de;

http://www.cell.com/developmental-cell/abstract/S1534-5807%2815%2900795-9