Humans are unable to regenerate heart muscle damaged by disease, unlike some animals such as zebrafish. Researchers have identified a set of genes in zebrafish that reactivate after heart damage and repair it. This discovery could lead to therapies that activate similar genes in humans for heart repair.

Scientists from the University of California, Berkeley, and the California Institute of Technology are investigating which upstream gene or genes trigger this gene circuit's reactivation. Once identified, CRISPR tools might be used to reactivate similar genes in humans after heart damage, as humans use the same set of genes during embryonic heart development.

“Zebrafish and humans are comparable in their cell types and how these cell types form during development," said Megan Martik, a UC Berkeley assistant professor of molecular and cell biology. "How can we harness what nature’s already figured out how to do in the zebrafish and apply it in a human context?”

The research was led by Berkeley graduate students Rekha Dhillon-Richardson and Alexandra Haugan. They discovered that zebrafish neural crest cells contribute to heart regeneration, unlike human neural crest cells. By using single-cell genomics on zebrafish neural crest cells, they identified key genes essential for post-injury reactivation.

“In both humans and zebrafish, we know that neural crest cells contribute to the heart... because the neural crest-derived cardiomyocytes in the zebrafish can respond to injury by regenerating and the same cells in humans can’t,” Martik explained.

CRISPR techniques were employed to identify crucial genes like egr1, which may play a role in regeneration. Enhancers activating these genes present promising targets for CRISPR-based therapies.

Martik is developing CRISPR techniques targeting gene enhancers in human-derived cardioids to explore therapeutic approaches. “There are so many advances...if we find the switch that can activate the necessary gene programs...it’d be completely feasible to develop a CRISPR therapeutic,” she said.

The work involved contributions from UC Berkeley's Luke Lyons and Joseph McKenna. The research received support from various foundations including the American Heart Association and National Institutes of Health.