Young at heart: novel temporal window of cardiac regeneration

A study carried out at CMR[B] in collaboration with IBEC and the UB has established that the ability of the heart to regenerate after a wound is related to the stiffness of its cellular environment and not only 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 a heart attack or stroke.

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

“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

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.

Now, for the first time, researchers have experimentally evaluated the regeneration ability of mice heart when heart tissue is amputated, 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 that 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 cardiomyocyte regeneration ability from its proliferation ability in neonatal mice.”

The stiffness of the environment, a limiting factor

Thanks to a collaboration with the IBEC-UB research group of Dr. Daniel Navajas, also linked to CIBER-BBN, 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 pharmacologically decreasing 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 mammal 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 frame of heart regeneration in neonates in such a specific way will ease the way for further in-depth analysis of the responsible mechanisms,” adds Dr. Ángel Raya, director of the Center for Regenerative Medicine of Barcelona (CMR[B]) and corresponding author. “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.

Source article: Mario Notari, Antoni Ventura-Rubio, Sylvia J. Bedford-Guaus, Ignasi Jorba, Lola Mulero, Daniel Navajas, Mercè Martí, Ángel Raya (2018). The local microenvironment limits the regenerative potential of the mouse neonatal heart. Science Advances, Vol. 4, no. 5, eaao5553