Sulf1 regulates inflammation via modulation of TGF-β dependent epicardial activation.

Unlike adult humans, zebrafish can regenerate their hearts after injury. After cardiac injury, the epicardium is rapidly activated to contribute both signaling factors and progenitor cells that are essential to establish a pro-regenerative niche. Concurrent with epicardial activation, cardiac injury triggers a robust inflammatory cascade. While the epicardial response is crucial for cardiac regeneration, the mechanisms by which it modulates the immune landscape remain largely unknown. Sulfatases have emerged as important modulators of inflammation through regulating cytokine and growth factor signaling. Here we find that the zebrafish epicardium upregulates the endo-sulfatase Sulf1 after injury. Using newly generated gain- and loss-of-function tools, we show that Sulf1 regulates epicardial activation and regeneration via TGF-β signaling. Abrogation of sulf1 results in cardiomyocyte regeneration defects and increased fibrosis. Moreover, disrupted TGF-β signaling in sulf1 mutants stimulates inflammation and macrophage recruitment. scRNA-seq analyses reveal that epicardial Sulf1 regulates the recruitment of pro-inflammatory macrophage subsets. Epicardial overexpression of sulf1 reverses TGF-β signaling and inflammation phenotypes. These data show that Sulf1 modulates TGF-β-dependent epicardial activation to regulate cardiac inflammation during heart regeneration.