Genetic Code Enables Zebrafish to Mend Damaged Organs

Zebrafish have the remarkable and rare ability to regrow and repair their hearts after damage. New research from Caltech and UC Berkeley has identified the circuit of genes controlling this ability and offers clues about how a human heart might someday be repaired after damage, such as a heart attack or in cases of congenital heart defects.

The research was a collaboration between the laboratories of Marianne Bronner, Caltech's Edward B. Lewis Professor of Biology and director of the Beckman Institute, and developmental biologist Megan Martik of UC Berkeley. A paper describing the study appears in the journal Proceedings of the National Academy of Sciences.

The heart is made up of many different kinds of cells, such as muscle, nerve, and blood vessel cells. In zebrafish, around 12 to 15 percent of these cells originate from a specific population of stem cells called neural crest cells. The Bronner and Martik laboratories have studied neural crest cells and their crucial role in development in many lab animal models, including zebrafish and lamprey. Humans also have analogous neural crest cells that give rise to varied cell types in almost every organ of the body ranging from cells of the facial skeleton to cells of the nervous system.

In the new study, the team found that the heart cells derived from neural crest cells are responsible for orchestrating the reconstruction process in damaged zebrafish hearts. When those neural crest–derived heart cells were removed in experiments, the hearts lost their ability to regenerate after damage. Importantly, the study identified the complex circuit of genes that is activated during regeneration. These genes, the researchers found, are crucial for normal embryonic development and then are inactivated during the animal's adult life—but are reactivated to enable tissue regeneration.

Next, the team aims to study how these cells reactivate such gene programs to answer the question: What signal triggers the activation of these genes after damage? Ultimately, the work could reveal whether humans could activate analogous genes if given that same signal. The Martik team is currently using CRISPR technology—a common gene-editing technique—on human heart cells in lab dishes to determine if these genes can be reactivated.

The paper is titled "Reactivation of an Embryonic Cardiac Neural Crest Transcriptional Profile During Zebrafish Heart Regeneration." The first authors are Rekha M. Dhillon-Richardson and Alexandra K. Haugan of UC Berkeley. In addition to Bronner and Martik, additional co-authors are Luke W. Lyons and Joseph K. McKenna of UC Berkeley. Funding was provided by the American Heart Association, the Shurl and Kay Curci Foundation, the National Institutes of Health, and the National Science Foundation. Bronner is an affiliated faculty member with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.