Secrets of zebrafish heart regeneration could transform human cardiac care

Zebrafish stand out for their remarkable ability to regenerate heart tissue. This amazing capability starkly contrasts with their evolutionary cousin, the medaka fish, and humans, who suffer permanent scars from heart attacks.

Zebrafish heart tissue regeneration is a captivating prospect for transformative advances in human cardiac care. A team of biologists at the University of Utah has explored the mechanisms underlying this fascinating regerative ability.

Cellular secrets of zebrafish heart regeneration

“Adult humans respond to heart injury by forming a permanent scar, yet other vertebrates are capable of robust and complete cardiac regeneration,” wrote the researchers.

“Despite progress towards characterizing the mechanisms of cardiac regeneration in fish and amphibians, the large evolutionary gulf between mammals and regenerating vertebrates complicates deciphering which cellular and molecular features truly enable regeneration.”

By examining the cardiac injury responses of the zebrafish, known for its regenerative capacity, and the medaka, which lacks this ability, the researchers set out to uncover the underlying mechanisms of cardiac repair.

“We thought by comparing these two fish that have similar heart morphology and live in similar habitats, we could have a better chance of actually finding what the main differences are,” explained study co-author Clayton Carey, a postdoctoral researcher.

The research, although not conclusive, pinpoints several potential factors – particularly within the immune system – that may explain the regenerative capabilities of the zebrafish. “It told us these two hearts that look very similar are actually very different,” noted Professor Jamie Gagnon, who led the research team

Experimental insights

To mimic heart attack conditions, the researchers used a cryoprobe. They crafted this device from copper wire and cooled it to extreme temperatures to selectively damage the fish’s heart tissue.

They then made observations at various intervals following the procedure to assess how each species responded to the injury.

In zebrafish, the researchers observed a vigorous immune response, similar to that seen during viral infections. This response was notably absent in medaka.

The role of the immune system

The study showed major differences in immune cell behavior. Specifically, macrophages migrated to the injury site in zebrafish much more than in medaka.

“Zebrafish have this immune response that is typical of what you might see during a viral infection, called an interferon response,” said Carey. Consequently, this response promotes new blood vessel growth and the replacement of damaged muscle with new cells.

“Our approach revealed key differences in both pre- and post-injury hearts that may be responsible for the contrasting regeneration outcomes. We found differences in immune cell recruitment and behavior, epicardial and endothelial cell signaling, and alterations in the structure and makeup of the myocardium,” wrote the researchers.

Reflections on evolutionary loss

Gagnon speculated that the ability to regenerate heart tissue might have been a common ancestral trait among teleosts. This group of ray-finned fish includes both zebrafish and medaka.

“My hunch is the ancestor of all animals could regenerate its heart after an injury, and then that’s been repeatedly lost in different types of animals,” said Gagnon. He expressed a desire to understand why such a beneficial trait would be lost over time.

Critical new insights into zebrafish heart regeneration

“Medaka and zebrafish have been used extensively as laboratory model vertebrates and have similar care requirements and body plans,” wrote the study authors. “While it was known that medaka are incapable of heart regeneration, it could have been assumed that medaka as fellow teleost fish would only have minor differences in cardiac structure.”

“Our study found a surprising number of distinguishing characteristics of the medaka heart compared to zebrafish. These differences included not only changes in cellular behaviors but also substantial changes in the structure of the myocardium itself.”

“Given the number of notable differences we observed between zebrafish and medaka, a wider phylogenetic survey of cardiac injury responses will be particularly useful to identify features that correlate with heart regeneration or non-regeneration across the teleost phylogeny.”

“These observations highlight how biodiversity within shorter evolutionary distances can enable comparative studies that reveal fundamental insights about the gain or loss of complex traits.”

Looking toward the future

The ultimate goal of the research is to use insights from zebrafish to develop treatments for human heart conditions.

“The more we learn about how animals can regenerate tissues, how those features have been lost in us and other animals, that’s going to help us think about our limitations and how we might engineer strategies to help us overcome those,” explained Gagnon.

The ongoing research opens new avenues for potential therapies in human medicine, perhaps even leading to a future where heart damage is fully reversible.

The study is published in the journal Biology Open.

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