In a recent study published in s Nature Cardiovascular Research, Rubén Marín Juez and Gülsüm Kayman Kürekçi reveal a fascinating mechanism that enables the zebrafish to regenerate its heart after an injury, such as one caused by a heart attack. Their work highlights the crucial role of a protein, Fibulin‑2, produced by cells located on the surface of the heart and essential for proper healing of damaged tissues. This discovery opens new avenues for improving cardiac repair in humans.

The Zebrafish, a Unique Model

In humans, a heart attack leaves a permanent scar with reduced contractility, impairing heart function. The zebrafish also develops fibrosis immediately after an injury, but this fibrotic tissue is temporary: it stabilizes the damaged area, supports the proliferation of new cardiac cells, and then gradually disappears. This ability to replace fibrotic tissue with new cardiac muscle makes the zebrafish an ideal model. “It can regenerate several organs throughout its life, which allows us to observe every stage of the process,” explains Gülsüm Kayman Kürekçi.

Fibulin‑2 and Nupr1b: The Challenge of Balance

How does zebrafish fibrosis eventually resolve? To answer this question, the team investigated how Fibulin‑2 functions. They tested two genetic models: one producing less of the protein, and one completely lacking it. When Fibulin‑2 levels were reduced, fibrosis persisted but in attenuated form, which resulted in better regeneration 90 days after injury. In contrast, when Fibulin‑2 was entirely absent, fibrosis became permanent and completely prevented heart regeneration. This finding reveals a key point: fibrosis is not something to eliminate, but something that must be precisely regulated.

To understand the dynamics behind the process, the team combined genetic tools with single cell sequencing. They identified a second essential protein: Nupr1b, this time located inside cardiac cells. While Fibulin‑2 acts in the extracellular environment, Nupr1b regulates the expression of genes involved in activating myofibroblasts, the cells that produce scar matrix. Together, the two proteins determine the timing and intensity of the fibrotic response, allowing the heart to stabilize without compromising its ability to rebuild itself.

Toward Therapeutic Applications?

This discovery is particularly promising because it suggests a way to modulate fibrosis upstream, more precisely than commonly envisioned strategies such as the use of direct TGF beta pathway inhibitors, which are often associated with significant side effects. To explore the therapeutic potential of Fibulin‑2, the team is already collaborating with researchers testing cardiac patches in mice that release this protein in a controlled manner. As Rubén Marín Juez reminds us: “The zebrafish offers us something unique: an adult heart that naturally regenerates. To understand how a heart heals, we need to think in terms of complementarity rather than opposition.” Between scarring and regeneration, the future may depend less on choosing one mechanism over the other than on learning how to harmonize them.

Photo (from left to right): Gülsüm Kayman Kürekçi, Rubén Marín Juez, Shaoqiu Zhang and Gursimran Kaur Bajwa © Courtesy