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Young at heart: a new window to cardiac regeneration

Image of the extracellular matrix of a heart with regeneration ability. In this case, a zebrafish heart was used for easier visualization. Image: CMR[B]

Image of the extracellular matrix of a heart with regeneration ability. In this case, a zebrafish heart was used for easier visualization. Image: CMR[B]

Photographs of hearts that underwent regeneration (one day heart at left hand) or that failed to regenerate and formed scar tissue (more than one day heart at right hand). Foto: CMR[B]

Photographs of hearts that underwent regeneration (one day heart at left hand) or that failed to regenerate and formed scar tissue (more than one day heart at right hand). Foto: CMR[B]

02/05/2018

Recerca

A new study conducted on neonatal mice carried out by the Center for Regenerative Medicine in Barcelona (CMR[B]), in collaboration with the Institute of Bioengineering of Catalonia (IBEC) and the University of Barcelona (UB), states that the ability of the heart to regenerate after a wound is related to the stiffness of the cellular environment, rather than to the proliferative capacity of the cardiac cells, narrowing the window of regeneration to forty-eight hours after birth. The study, published in Science Advances, , paves the way for the development of therapies based on the pharmacological modification of the extracellular matrix to promote tissue regeneration after myocardial infarction.

"We are now  beginning to understand that the extracellular matrix plays an important role in the behavior of stem cells and their therapeutic applications in regenerative medicine”, say the authors of the study. "The intracellular events regulated by genes and proteins have always been considered the main object of study so far. However, we lack a broader vision that encompasses all the main characters in the cardiac tissue regeneration ".

48 hours to regenerate

So far, the regeneration potential of cardiomyocytes ─heart cells─ was associated with their ability to proliferate. Previous studies had found that neonatal mice could be able to regenerate their heart after a wound up to seven days after birth, when heart cells are still under development.

For the first time, these researchers from Barcelona have experimentally evaluated the regeneration ability of the mouse’s heart, within a period from 24 hours to nine days after birth. "If the regenerative capacity of the neonatal heart depended only on the proliferation potential of the cardiac cells, we would have observed regeneration several days after birth, as it had been theorized, but this was not the case”, explains Dr Mario Notari, first author of the paper. "Instead, we were able to narrow this temporal window of regeneration to two days, showing that after 48 hours, the heart loses the ability to regenerate, although it is still developing. Thus, we have separated heart regeneration ability from cardiomyocyte proliferation ability in neonatal mice."

The stiffness of the environment, a limiting factor

Thanks to the collaboration with the IBEC-UB research group of Dr Daniel Navajas, member of the the Institute of Nanoscience and Nanotechnology (IN2UB) and to the Biomedical Research Networking Center (CIBER)  the researchers conducted the transcriptomic and mechanical analysis of the heart at 24 and 48 hours after birth. The main difference they observed was a significant increase in the stiffness of the extracellular matrix, which surrounds the cardiomyocytes, two days after birth.

After giving mice drugs to decrease this stiffness, the research team managed to extend the regeneration ability of the heart up to three days after birth. "Our results suggest that the composition and stiffness of the extracellular matrix are a limiting mechanism when it comes to the regenerative competence of the mammalian heart, which becomes an interesting line of research to work on" says Notari.

A new approach for the treatment of cardiovascular diseases

"Narrowing the time window of heart regeneration in neonates in such a detailed manner will ease the way for further in-depth analysis of the mechanisms that cause it”, adds Dr Ángel Raya, ICREA Research Professor and director of CMR[B] , last author of the study. "In any case, these findings pave the way for the development of new therapies for cardiovascular diseases based on regenerative medicine”. In the long run, reducing the stiffness of the cellular microenvironment could become a potential therapy for the treatment of cardiovascular pathologies.

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