A broken heart will mend over time. However, this isn’t the case for heart tissue following a heart attack. While skin and many other tissues of the body retain the ability to repair themselves after injury, the heart lacks this ability. Heart cells rapidly divide during embryonic and fetal development to form cardiac tissue and the myocardium. However, when heart cells mature in adulthood, they reach a terminal state where they can no longer divide.
Repairing cardiac muscle after a heart attack is at the forefront of heart research, and researchers have been investigating ways to persuade heart muscle cells to regenerate. Now, biomedical engineers at Duke have developed a novel strategy from an unlikely place—cancer.
In their new study published in Science Advances in an article titled, “Time-dependent Effects of BRAF-V600E on Cell Cycling, Metabolism, and Function in Engineered Myocardium,” the Duke researchers harnessed a powerful mutation found in melanoma that can push heart muscles to multiply in laboratory models of heart tissue.
“Mature heart muscle cells do not typically divide, so we thought we’d need an especially strong genetic mutation to convince them to multiply,” said Nenad Bursac, PhD, professor of biomedical engineering at Duke. “MAPK is a well understood pathway that, when mutated, can be pretty aggressive at inducing proliferation in cancers, which is why we chose to look into it.”
In the study, Bursac and PhD student Nicholas Strash studied neonatal rat heart cells grown within a 3D hydrogel environment. Developed by the laboratory over more than a decade, the hydrogel environment provides the cues to grow and mature cells into adult-like heart muscle tissues, where cell division naturally stops.
In an attempt to get the muscle to divide and grow again, the researchers infected it with a virus loaded with a mutated BRAF gene. Following its normal behavior, the virus inserted the mutated gene into the cells, causing it to become a part of the cells’ DNA. The researchers then introduced a drug that caused the mutated BRAF genes to activate.
As with skin cancer, once activated, the mutant genes caused the heart muscle cells to enter DNA synthesis, but not without drawbacks.
“Once the cells started entering into their multiplication phase, they also began disassembling the machinery that allows them to contract and pump blood when in the heart,” Strash said. “It caused the tissue as a whole to lose about 70% of its contractile strength, which is pretty dramatic. One reason for this is that almost all cells in the tissue got infected by the virus.”
With the accompanying loss of strength, the dosage and duration of gene activation needs to be precisely controlled—thus there’s much to do before any potential use in human patients.
The researchers will have to apply a different delivery system that can deliver the genes to the correct cells in a way that clinicians can fully control. Another obstacle in the way will be determining how to jump-start heart tissue regeneration without causing the tissue to lose strength.
The researchers believe there may be a window in which the mutated gene activity could be stopped after the replication begins, but before the contractile machinery is affected in a large portion of the heart. Or there may be an opportunity to administer a second therapeutic that could prompt the cells to rebuild the dismantled pumping machinery after proliferation.
Looking toward the future, the researchers are planning to study how this strategy works in the hearts of live animals and compare it to their lab-tested results. Working with live animals will also provide a better understanding of what other genes and processes are activated by the mutated BRAF gene.
“The heart essentially does not have primary cancers, and it’s almost unique that it doesn’t,” Bursac said. “Introducing this cancer mutation in the heart is obviously an engineered outcome that doesn’t happen naturally. Studying it in lab-grown tissues is a great step toward understanding what this entire signaling pathway does within the heart, which could have benefits beyond regenerative therapies.”