MicroRNA Treatment Prompts Cardiomyocyte Proliferation

Working with a variety of mouse models, heart diseases researchers showed that a hydrogel delivery system could release a specific microRNA at the site of injury following a myocardial infarction where it induced cardiomyocyte proliferation and tissue regeneration.

MicroRNA-based therapies that target cardiomyocyte proliferation have great potential for the treatment of myocardial infarction. MicroRNAs (miRNAs) are a family of noncoding 19- to 25-nucleotide RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) in a sequence specific manner, inducing translational repression or mRNA degradation, depending on the degree of complementarity between miRNAs and their targets. Many miRNAs are conserved in sequence between distantly related organisms, suggesting that these molecules participate in essential processes. In fact, miRNAs have been shown to be involved in the regulation of gene expression during development, cell proliferation, apoptosis, glucose metabolism, stress resistance, and cancer.

Following up previous studies showing that the miR-302/367 cluster regulated cardiomyocyte proliferation in the prenatal and postnatal heart, investigators at the University of Pennsylvania (Philadelphia, USA) developed an injectable hyaluronic acid hydrogel for the local and sustained delivery of miR-302 mimics to the heart.

The investigators injected this gel, into the heart muscles of three different populations of mice: (1) normal, healthy mice, (2) "Confetti mice," which had been genetically engineered so that individual cardiomyocytes randomly expressed one of four different fluorescent proteins, and (3) mice in which heart attacks were induced so that clinically relevant outcomes of the treatment could be studied. The encapsulated microRNAs were protected from degradation, maximizing the time period that they could be effective without the risk of damaging off-target cells.

Results published in the November 27, 2017, online edition of the journal Nature Biomedical Engineering revealed that a single injection of the hydrogel in the mouse heart led to local and sustained cardiomyocyte proliferation for two weeks. After myocardial infarction, gel–miR-302 injection caused local clonal proliferation and increased cardiomyocyte numbers in the border zone of the Confetti mouse model. In the Confetti mice, single red, yellow, or green cardiomyocytes progressed to clusters, ranging from two to eight cells of the same color.

The mice injected following induced heart attack showed improved recovery as compared to controls, including higher ejection fraction (more blood pumped with each beat) and smaller increases in heart size.

"We want to design the right material for a specific drug and application," said senior author Dr. Jason Burdick, professor of bioengineering at the University of Pennsylvania. "The most important traits of this gel are that it is 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. 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."

"We are seeing a change in approaches for regenerative medicine, using alternatives to stem cell delivery," said Dr. Burdick. "Here, instead of introducing new cells that can have their own delivery challenges, we are simply turning on repair mechanisms in cells that survive injury in the heart and other tissues."

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