Single-cell analysis of mast cell populations across organs reveals insights into cell origins, anatomical niches and neuron-associated functions.

Abstract Mast cells (MCs) are heterogenous tissue-resident immune cells associated with blood vessels and neurons. However, the extent to which specialized MCs can exhibit micro-environment-specific functions is unclear. Using single cell RNA sequencing, we characterize connective tissue-type and mucosal MCs across organs and found that they can be discriminated based on MrgprB2 expression. While MrgprB2+ connective MCs are enriched in neuroreceptors, develop during the embryogenesis and renew independently of the bone marrow (BM); MrgprB2neg mucosal MCs arise postnatally, are sensitive to signals from the microbiome and renewed by BM progenitors. Importantly, MrgprB2+, but not MrgprB2neg MCs are required for food-induced anaphylactic shock. In the gut, MrgprB2+ MCs occur in contact with substance P-secreting enteric neurons and the specific depletion of either MrgprB2+ MCs or substance P results in dysregulation of gut contractions. Thus, we demonstrate that two independent MC populations exist in multiple organs, with different developmental dynamics and biological programming.