# Mammalian mesenchymal stromal cells enhance zebrafish fin regeneration

## TL;DR

This study shows that mammalian mesenchymal stromal cells boost zebrafish fin regeneration by boosting macrophage activity and using prostaglandin E2.

## Contribution

The novel finding is that MSC-derived PGE2 is essential for regeneration by modulating macrophage behavior and promoting MSC persistence.

## Key findings

- MSCs enhance fin regeneration by increasing early recruitment of inflammatory macrophages.
- PGE2 inhibition abolishes the regenerative effect of MSCs and increases macrophage levels.
- PGE2-inhibited MSCs are more susceptible to phagocytosis despite maintaining viability.

## Abstract

Mesenchymal stromal cells (MSCs) possess well-described immunoregulatory properties, yet their capacity to drive regeneration in vertebrates is still debated and their mechanisms of action remain to be fully elucidated. In this study, we used zebrafish larvae, a highly regenerative vertebrate model to study the effects of MSC delivery on caudal fin fold regeneration and monitored macrophage dynamics through live imaging in fluorescent reporter lines. We found that MSCs enhanced fin regeneration by increasing the early recruitment of inflammatory (tnfa +) macrophages at 1-day-post-amputation (dpA), and accelerating resolution between 2 and 3 dpA. Given the established role of prostaglandin E2 (PGE2) in MSC-mediated immunoregulation, we examined its contribution using indomethacin, a cyclooxygenase inhibitor that suppresses PGE2 production in grafted MSCs. We observed that PGE2 inhibition abolished the pro-regenerative effect of MSCs and maintained elevated tnfa + macrophage levels. PGE2-inhibited MSCs were more susceptible to phagocytosis by both zebrafish and mammalian macrophages, while maintaining viability, indicating a loss of PGE2-mediated protection in treated cells. Together, these findings demonstrate that MSC-derived PGE2 is essential for MSC regenerative function by promoting MSC persistence and modulating macrophage behavior, highlight the zebrafish as a powerful in vivo platform to dissect stem cell–immune interactions and optimize MSC-based regenerative strategies.

The online version contains supplementary material available at 10.1186/s13619-025-00273-7.