REGENERATING DAMAGED HEART TISSUE

By Brian Maffly

UNLIKE HEART ATTACKS IN HUMANS, MANY ANIMALS CAN CLEAR CARDIAC SCAR TISSUE AND REGROW DAMAGED MUSCLE AS ADULTS, A TOOL SCIENTISTS ARE SEEKING TO REPLICATE TO ADVANCE TREATMENT OF CARDIAC PATIENTS.

Led by Jamie Gagnon, his team compared zebrafish, which can regenerate its heart, with medaka, which cannot. Both come from the teleost family of ray-finned fish, descended from a common ancestor. Gagnon suspects heart regeneration is an ancestral trait common to all in the family, so understanding their evolution is key. If the reason a subject would lose this advantage is found, a way to replicate it could follow.

The team used a device to injure the fish hearts in ways that mimic human heart attacks. A copper wire cryoprobe was used to make tiny incisions, then applied to the edge of the heart. Ninety-five percent of fish survive this process, allowing this regeneration to take place. After three or fourteen days, their hearts were extracted and dissolved into a single-cell solution, to be subjected to RNA sequencing in search of markers indicating the response to the injury.

“Zebrafish have this immune response that is typical of what you might see during a viral infection, called an interferon response,” says Clayton Carey, a postdoctoral researcher and lead author of a published study in Biology Open. “That response is completely absent in medaka.”

Differences were documented in immune cell recruitment and behavior, epicardial and endothelial cell signaling, and alterations in the structure and makeup of the heart. The indication is that this regeneration is sourced in the immune system, as more macrophages (specialized immune cells), migrated to the wound site for zebrafish.

This response forms a transient scar that doesn’t calcify. “What you do with that scar is what matters,” Gagnon says. “We think the interferon response causes these macrophage cells to promote the growth of new blood vessels.” Over time new muscle replaces the damaged cardiac tissue and the heart heals.

“The more we learn about how animals can regenerate tissues will help us think about our limitations, how we might engineer strategies to help us overcome them,” says Gagnon. “Our hope is that we build this knowledge base in animals that can be studied in detail, then use that knowledge to generate more focused experiments in mammals, and then maybe someday in human patients.”