Alpha-1 adrenergic signaling drives cardiac regeneration via extracellular matrix remodeling transcriptional program in zebrafish macrophages

The autonomic nervous system plays a pivotal role in cardiac repair. Here, we describe the mechanistic underpinning of adrenergic signaling in fibrotic and regenerative response of the heart to be dependent on immunomodulation. A pharmacological approach identified adrenergic receptor alpha-1 as a key regulator of macrophage phenotypic diversification following myocardial damage in zebrafish. Genetic manipulation and single-cell transcriptomics showed that the receptor signals activation of an "extracellular matrix remodeling" transcriptional program in a macrophage subset, which serves as a key regulator of matrix composition and turnover. Mechanistically, adrenergic receptor alpha-1-activated macrophages determine activation of collagen-12-expressing fibroblasts, a cellular determinant of cardiac regenerative niche, through midkine-mediated paracrine crosstalk, allowing lymphatic and blood vessel growth and cardiomyocyte proliferation at the lesion site. These findings identify the mechanism of adrenergic signaling in macrophage phenotypic and functional determination and highlight the potential of neural modulation for regulation of fibrosis and coordination of myocardial regenerative response.