Scientists may have found a way to regenerate heart muscles following a heart attack.
Researchers from the University of Pennsylvania created an injectable gel that that slowly releases short gene sequences called microRNAs into the heart muscle, restarting replication in existing cardiomyocytes—contractile cells in the heart.
The microRNAs targeted signaling pathways are related to cell proliferation and were able to inhibit some of the inherent stop signals that keep cardiomyocytes from replicating, resulting in cardiomyocytes reactivating their proliferative potential.
The researchers found that with more heart cells dividing and reproducing, mice treated with the gel after a heart attack showed improved recovery in key clinically relevant categories.
“Biologic drugs turn over very fast,” Edward Morrisey, a professor in Medicine at Penn, a member of the Cell and Molecular Biology graduate group and scientific director of the Penn Institute for Regenerative Medicine in Penn Medicine, said in a statement. “The microRNAs that we used last less than eight hours in the bloodstream, so having a high local concentration has strong advantages.”
The short lifespan indicates that if patients were treated systemically they would need to be injected frequently with large doses to ensure that a sufficient amount of microRNAs reaches their target in the heart.
The cells that contract the heart muscle and enable it to beat do not regenerate in mammals after an injury. Following a heart attack there is a dramatic loss of the heart muscle cells, which those that survive cannot effectively replicate.
Fewer of the cardiomyocytes means the heart pumps less blood with each beat, leading to the increased mortality associated with heart disease.
“We want to design the right material for a specific drug and application,” Jason Burdick, a professor in Bioengineering at Penn, said in a statement. “The most important traits of this gel are that it’s shear-thinning and self-healing.
“Shear-thinning means it has bonds that can be broken under mechanical stress, making it more fluid and allowing it to flow through a syringe or catheter,” he added. “Self-healing means that when that stress is removed, the gel’s bonds re-form, allowing it to stay in place within the heart muscle.”
The gel features attachment sites that keep the microRNAs in place and as the gel breaks down, it loses its grip on the microRNAs, which can slip out of the gel and into the cardiomyocytes.
While encapsulated, the microRNAs are also protected from degradation, maximizing the period that they can be effective without the risk of them invading off-target cells.
“There’s likely a time window that the cardiomyocytes are susceptible to this stimulus—maybe a week or two after injury,” Morrisey said. “We want to promote proliferation for a short period and then stop.”
The researchers tested the gel with normal, healthy mice, genetically engineered mice that have individual cardiomyocytes that randomly express one of four different fluorescent proteins and mice in which heart attacks were induced so that clinically relevant outcomes of the treatment could be studied.
Within a few days after injecting the gel, the heart tissue of the healthy mice showed increased biomarkers of cardiomyocyte proliferation.
For the mice expressing different fluorescent proteins, after inducing heart attacks and introducing the gel, the researchers saw that single red, yellow or green cardiomyocytes had become clusters, ranging from two to eight cells of the same color.
The third group of mice showed improved recovery as compared to controls, including higher ejection fraction—more blood pumped with each beat—and smaller increases in heart size.
The researchers will now test the gel on human heart cells in vitro and conduct physiological experiments in animals with more human-like hearts, including pigs.
The study was published in Nature Biomedical Engineering.
