Administering “young matrix” molecules to damaged mouse hearts led to muscle repair.
Research at the Weizmann Institute of Science has uncovered a molecule in newborn hearts that appears to control the renewal process. When injected into adult mouse hearts injured by heart attacks, this molecule, called agrin, seems to “unlock” that renewal process and enable heart muscle repair.

These findings, published in the journal Nature, are already pointing to new directions for research on restoring the function of damaged hearts.

Prof. Eldad Tzahor, who led the study together with doctoral student Elad Bassat, research student Alex Genzelinakh and other team members in the Weizmann Institute’s Molecular Cell Biology Department, explains that following a heart attack in humans, the healing process is long and inefficient. Once damaged, muscle cells called cardiomyocytes are replaced by scar tissue, which is incapable of contracting and thus cannot participate in pumping. This, in turn, leads to further stress on the remaining muscle and eventual heart failure.

The researchers found that the younger extracellular matrix (ECM), in contrast to the older, elicited cardiomyocyte proliferation.

A screening of ECM proteins identified several candidate molecules for regulating this response, among them Agrin. Agrin was already known for its effects on other tissues – particularly in the neuromuscular junction, where it helps regulate the signals passed from nerves to muscles. In mouse hearts, levels of this molecule drop over the first seven days of life, suggesting a possible role in heart regeneration. The researchers then added Agrin to cell cultures and noted that it caused the cells to divide.

Next, the researchers tested Agrin on mouse models of heart injury, asking whether it could reverse the damage. Indeed, they found that following a single injection of Agrin mouse hearts were almost completely healed and fully functional, although the scientists were surprised to find that it took over a month for the treatment to impart its full impact on cardiac function and regeneration. At the end of the recovery period, however, the scar tissue was dramatically reduced, replaced by living heart tissue that restored the heart’s pumping function.

In other words, Tzahor speculates that in addition to causing a certain amount of direct cardiomyocyte renewal, Agrin somehow affects the body’s inflammatory and immune responses to a heart attack, as well as the pathways involved in suppressing the fibrosis, or scarring, which leads to heart failure. The length of the recovery process, however, is still a mystery, as the Agrin, itself, disappears from the body within a few days of the injection.

“We discovered that it attaches to a previously unstudied receptor on the heart muscle cells, and this binding takes the cells back to a slightly less mature state – closer to that of the embryo – and releases signals that may, among other things, initiate cell division.”

Experiments with mice that were genetically engineered to lack Agrin in their hearts further support this idea: In its absence, newborn mice could not properly regenerate heart tissue following injury. Because mice cannot live without the other functions of Agrin, this was a technically challenging experiment to perform, adds Tzahor.

The team then proved that Agrin has a similar effect on human heart cells grown in culture. He and his team are now working to understand exactly what happens in the period of time between the injection of Agrin and the return of full cardiac functionality. In addition, members of Tzahor’s team have started pre–clinical studies in larger animals in Germany in collaboration with Prof. Kupatt of the Technical University of Munich to determine the effect of Agrin on cardiac repair.