How Zebrafish Mend a Broken Heart

Zebrafish hearts can take a licking and keep on ticking. Even if they lose up to 20% of a ventricle, the animals form a clot that stops bleeding within seconds and then gradually replace the lost tissue. Within a month or so, they are back to normal. The impressive repair work is accomplished not by stem cells in the heart but by mature heart cells, two new studies suggest. Figuring out exactly how the animals accomplish their self-repair could help scientists find ways to trigger similar regeneration in human patients.

A long-standing question for scientists who study zebrafish, salamanders, and other animals that can regrow lost parts is whether the animals activate and recruit stem cells to make the repair or whether they trigger their mature cells to start dividing again, says Elly Tanaka, a developmental biologist at the Center for Regenerative Therapies at the University of Technology Dresden in Germany. The new papers clearly show that for zebrafish hearts, mature cells are doing most of the rebuilding, she says.

To pinpoint where the newly grown heart cells were coming from, developmental biologist Juan Carlos Izpisúa Belmonte and his colleagues at the Center of Regenerative Medicine in Barcelona, Spain, and the Salk Institute in San Diego, California, developed zebrafish in which cardiomyocytes—mature heart muscle cells—glow green under fluorescent light. They removed 20% of the animals’ ventricle—considered the maximum survivable injury--and observed the fish as they repaired the wound.

In tomorrow’s issue of Nature, the team reports that the new heart tissue also glowed green, indicating that it originated from the tagged cells rather than from unlabeled immature stem cells. Further experiments showed that the cardiomyocytes near the injury site seem to take a step backward in development, detaching from one another and losing their typical shape—presumably to make it possible for them to start dividing again as they replenish the lost tissue.

Similar experiments by Kenneth Poss of Duke University in Durham, North Carolina, and his colleagues also suggest that mature cardiac muscle cells are the source of the zebrafish’s heart-repair kit. The researchers developed zebrafish in which cells turn green when they express a gene called gata4, which is turned on in embryonic hearts. In a second paper that will be published tomorrow in Nature, they report that after they removed part of a fish’s heart, mature cells near the injury turned on gata4. The cells then started to divide and gave rise to the new heart tissue. Within 2 weeks, the new heart tissue was receiving electrical signals along with the healthy heart tissue. The next step, both teams say, is to identify the cellular signals that trigger the regrowth.

Izpisúa Belmonte says that the de-differentiated cells he and his colleagues observed resemble so-called “hibernating cardiomyocytes” that scientists have observed in damaged mammal hearts. “The cells de-differentiate in a very similar way to zebrafish, but they don’t go to the next step, they don’t proliferate,” he says. He and his colleagues are testing different factors in mice to see if they can get around whatever is preventing the cells from dividing and making new tissue. “It seems that mammals try to [regenerate] as well. So maybe it isn’t so different after all,” he says.