# Attenuation of epicardial activation and myofibroblast abundance via the Fbln2–Nupr1b axis stimulates cardiac regeneration in zebrafish

## TL;DR

The study shows how fibulin-2 and nuclear protein 1b control heart regeneration in zebrafish by managing fibrosis after injury.

## Contribution

The novel finding is the identification of the Fbln2–Nupr1b axis as a regulator of epicardial cell activation and regeneration.

## Key findings

- Fibulin-2 regulates activated epicardial cells to balance fibrosis and regeneration.
- Nupr1b controls myofibroblast abundance and rescues fbln2 mutant phenotypes.
- Modulating the Fbln2–Nupr1b axis enhances cardiac regeneration in zebrafish.

## Abstract

After injury, the adult human heart fails to regenerate and forms a persistent fibrotic scar. By contrast, fibrosis is transient in the injured zebrafish heart, facilitating cell recruitment and providing regenerative cues. The mechanisms that restrain excessive fibrosis while enabling regeneration remain poorly understood. Here we show that fibulin-2 (Fbln2) regulates specific populations of activated epicardial cells to balance the response to cardiac injury. Using genetic tools for Fbln2 dosage, we find that attenuation of epicardial activation stimulates regenerative programs. Mechanistically, we identify epicardial nuclear protein 1b (Nupr1b) as an Fbln2 effector. Using gain- and loss-of-function approaches, we show that Nupr1b controls epicardial myofibroblast abundance. Notably, epicardial-specific overexpression of nupr1b rescued fbln2 mutant phenotypes. These findings shed light on how modulation of epicardial cell state transitions through Fbln2–Nupr1b signaling regulates regenerative responses after cardiac injury.

Kayman Kürekçi et al. show that fibulin-2 regulates epicardial cell activation through nuclear protein 1b signaling to balance fibrosis and regeneration after cardiac injury, and modulating this pathway can enhance heart regeneration in zebrafish.