Alpha-1 adrenergic signaling drives cardiac regeneration through activation of extracellular matrix remodeling transcriptional program in macrophages

Autonomic drive plays a pivotal role in cardiac regeneration. Sympathetic or cholinergic denervation impairs myocardial regrowth in neonatal mouse and zebrafish hearts. Here, we uncovered the mechanistic underpinning of adrenergic signaling in regenerative repair of the heart to be critically dependent on immunomodulation. Through pharmacological and genetic manipulations, we identified adrenergic receptor alpha-1 as a key regulator of macrophage phenotypic diversification following myocardial infarction in zebrafish. Single-cell transcriptomics revealed that the receptor signals activation of an ‘extracellular matrix remodeling’ transcriptional program characterized by upregulation of matrix proteins and matrix-modifying enzymes in a macrophage subset. Functionally, adrenergic receptor alpha-1-activated macrophages regulate fibrotic response of the heart by mediating collagenous extracellular matrix turnover and myofibroblast activation, allowing vascularization and cardiomyocyte cell cycle entry at the infarcted lesion. These findings not only unravel the mechanism of adrenergic signaling in macrophage phenotypic and functional determination, but also highlight the potential of neural modulation for regulation of fibrosis and coordination of myocardial regenerative response. Zebrafish hearts subjected to cryoinjury were collected at 7 dpi, dissociated and live cells ,sorted by FACS, analyzed with scRNAseq