Pheromone-dependent olfaction bidirectionally regulates muscle extracellular vesicles formation

Extracellular vesicles (EVs), entities transporting a variety of cargo, are directly involved in many biological processes and intercellular communication, the characterization of which requires studying multi-tissue organisms. We previously demonstrated that the largest evolutionarily conserved EVs, exophers, are a component of the C. elegans maternal somatic tissue resource management system, and their formation is induced by the embryos developing in utero. In this study, we explored inter-tissue regulatory networks of exophergenesis. We found that exophergenesis activity is differentially modulated by sex-specific ascaroside (pheromones) signaling molecules, known to have multiple functions in development and behavior. While hermaphrodite-released pheromones down-regulate exophergenesis, male- released pheromones favor strong exopher production. This ascaroside-dependent regulation is fine-tuned by exopher-promoting olfactory neurons exposed to the environment and exopher- inhibiting sensory neurons exposed to the body cavity. Therefore, we uncovered critical control nodes for muscle exophergenesis in response to environmental and internal conditions. Our findings may imply the existence of an analogous mechanism regulating cardiomyocyte exophers, which contributes to the olfactory dysfunction-dependent risk of cardiovascular disease in humans.