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

Abstract

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. Sulf1 is a critical modulator of cardiac regeneration through its dual role in controlling TGF-β-dependent epicardial activation and shaping the inflammatory response. Our data establish the Sulf1-TGF-β axis as a driver of both epicardial and immune responses after injury. The epicardium upregulates sulf1 in response to cardiac injury and this induction is required for TGF-β mediated epicardial activation. Sulf1 regulates epicardial TGF-β signaling to facilitate cardiomyocyte regeneration and limit late-stage fibrosis. Sulf1 mediated TGF-β signaling modulates the macrophage response after cardiac injury. Epicardial Sulf1 regulates the epicardial-immune crosstalk during regeneration. The epicardium upregulates sulf1 in response to cardiac injury and this induction is required for TGF-β mediated epicardial activation. Sulf1 regulates epicardial TGF-β signaling to facilitate cardiomyocyte regeneration and limit late-stage fibrosis. Sulf1 mediated TGF-β signaling modulates the macrophage response after cardiac injury. Epicardial Sulf1 regulates the epicardial-immune crosstalk during regeneration. Sulf1 is a critical modulator of cardiac regeneration through its dual role in controlling TGF-β-dependent epicardial activation and shaping the inflammatory response. Our data establish the Sulf1-TGF-β axis as a driver of both epicardial and immune responses after injury.