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Young at heart: a novel window to cardiac regeneration

Young at heart: a novel window to cardiac regeneration

A new study in 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), has established 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 48 hours after birth. The research, 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. .

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

48 hours to regenerate

Up until now, the regeneration potential of cardiomyocytes - heart cells - was associated with their ability to proliferate. Previous studies made it possible to theorize 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, CMR[B] researchers have experimentally evaluated the regeneration ability of the mouse heart, from 24 hours to nine days after birth. "If the regenerative capacity of the neonatal heart only depended on the proliferation potential of cardiac cells, we would have observed regeneration several days after birth, as 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 disconnected 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, together with the CMR[B] group also linked to the Center Network for Biomedical Research (CIBER), the researchers carried out the transcriptomic and mechanical analysis of the heart at 24 and 48 hours after birth. The main difference 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 responsible mechanisms”, adds Dr. Ángel Raya, ICREA Research Professor and CMR[B] Director, corresponding 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, decreasing the stiffness of the cellular microenvironment could become a potential therapy for the treatment of cardiovascular pathologies. .

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