Mexican fish shed light on lrrc10—a gene that could be key to heart repair

Scientists at the University of Oxford are pitching cardiologists a new model for heart regeneration research: the Mexican tetra fish, a blind, translucent animal with an innate ability to repair its damaged heart tissue.

Mathilda Mommersteeg, PhD, an associate professor of developmental and regenerative medicine at Oxford, and colleagues can trace the tetra fish back more than a million and a half years, to the waterways of Northern Mexico. The seasonal ebb and flow of floodwaters meant some of the fish were washed into caves while others remained in the river, on the surface. The “cave fish” lost their color, eyesight and ability to regenerate heart muscle—all things “surface fish” retained.

Interested in which biological mechanisms were responsible for the loss of function in cave fish, Mommersteeg and her team bred both surface and cave fish in the lab, performing surgery on select fish to remove pieces of their heart and observing which animals were able to repair that damage.

“Comparing the natural regenerative and scarring response within the same species would avoid confounding physiological factors and allow [for identification of] the key mechanisms driving regeneration, aiding the translation of advances in our understanding of fish heart regeneration to human,” Mommersteeg and co-authors wrote in Cell Reports, where they published their findings Nov. 20.

The researchers found that while surface fish were able to regenerate their hearts, some cave fish were unable to do so. Instead, they formed a permanent scar.

Mommersteeg et al. studied the gene activity in both fish and were able to identify three areas of the genome that were implicated in the tetra fish’s ability to repair their hearts. Two genes in particular, lrrc10 and caveolin, were much more active in surface fish than cave fish.

Since lrrc10 has previously been linked to dilated cardiomyopathy in humans and the process of heart cell contraction, the researchers focused on that gene. They studied its effect by inactivating lrrc10 in zebrafish, who also have the ability to regenerate their hearts, and found the zebrafish could no longer repair their cardiac tissue fully.

The team also cross-bred cave and surface fish and found their offspring exhibited different levels of ability to regenerate heart tissue, indicating the lrrc10 link is heritable.

“Here, we show that Astyanax mexicanus (tetra fish) cave fish and surface fish respond differently to cardiac injury,” they wrote. “This not only allows us to compare the regenerative and scarring response within one species, but also provides the opportunity to link the capacity for heart regeneration directly to the genome using forward genetic screening.”