Why can zebrafish heal heart damage, unlike other fish?

Single-cell profiling identifies unique aspects of regenerating hearts.

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Some animals can heal their hearts after damage, unlike humans, who develop permanent scars from heart attacks. Scientists study this ability in creatures like fish and amphibians to improve treatments for human heart patients.

At the University of Utah, biologists led by Jamie Gagnon compared zebrafish, which regenerate heart tissue, with medaka, which does not. They found potential reasons for how zebrafish can repair their hearts, primarily related to the immune system. Postdoctoral researcher Clayton Carey, lead author of the study, highlighted the importance of comparing these fish to understand their differences in heart-healing abilities.

Gagnon’s team still needs to solve the mystery, but their study revealed new insights into how zebrafish regenerate their hearts. The research showed that despite looking similar, the hearts of zebrafish and medaka are very different.

Both fish, belonging to the ray-finned teleost family and originating from an everyday ancestor millions of years ago, have small bodies and live in freshwater with two-chamber hearts. Medaka are from Japan, while zebrafish are from the Ganges River basin.

Image showingMedaka, a small freshwater fish from Japan, is used in evolutionary research in the lab of University of Utah biologist Jamie Gagnon.
Medaka, a small freshwater fish from Japan, is used in evolutionary research in the lab of University of Utah biologist Jamie Gagnon.. Credit: BRIAN MAFFLY.

The study suggests that comparing non-regenerating and regenerating fish can help identify unique cellular traits related to heart regeneration. Gagnon believes heart regeneration could be a trait inherited from a common ancestor among all teleost fish.

Studying why some fish can’t regenerate could help us understand why mammals can’t. Zebrafish are popular as pets in the US due to their distinctive stripes. Biologists began using them in the 1970s to study how vertebrates develop before birth.

Zebrafish are ideal for research because they breed quickly in labs, are easy to study, and are resilient. To mimic heart attacks, the Gagnon lab used a cryoprobe to injure fish hearts and then learned how zebrafish and medaka responded over time.

Carey used a cryoprobe from copper wire cooled to -170°C in liquid nitrogen. The team made minor cuts in the fish’s bellies to expose their hearts, applying the probe for 23 seconds. While 95% of fish survived briefly, hearts were removed after three or 14 days and dissolved for RNA sequencing.

They found that zebrafish triggered an interferon response akin to viral infections, which was absent in medaka. Differences in immune cell behavior, heart cell signaling, and muscle composition were noted; medaka lacked specific muscle cells in zebrafish.

Gagnon believes ancient animals could regenerate hearts, a trait lost over time in various species. He questions why this ability disappeared. His lab at the University of Utah studies medaka, a Japanese fish, for insights into evolution. Zebrafish regenerate hearts differently, involving their immune system. More specialized immune cells migrate to wounds in zebrafish compared to medaka.

Zebrafish also form a temporary scar that promotes new blood vessels and muscle growth, aiding in heart repair. Understanding these mechanisms may inspire treatments for human patients by overcoming our natural limitations through engineered strategies.

Journal reference:

  1. Clayton M. Carey, Hailey L. Hollins et al., Distinct features of the regenerating heart uncovered through comparative single-cell profiling. Biology Open. DOI: 10.1242/bio.060156.

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