A sensitive method for profiling cell-type-specific secretomes of rare cells from complex tissues.

Very rare cells often have outsized physiologic functions. However, their low abundance presents a technical challenge for studying their function. Here, we generate a murine model, which enables the profiling of secreted proteomes (secretomes) from physiologically relevant low-abundance cells in complex tissues, without the use of viral vectors. We then deploy this model to profile the secretomes of two rare innate immune cell types: Kupffer macrophages from whole liver and the rare airway microfold (M) cells in cultures of differentiated airway epithelia. The method we have developed is characterized by remarkable sensitivity, capturing cell-specific proteins that were not captured in single-cell RNA sequencing (scRNA-seq) atlases. We have made this genetic secretome mouse model available to the community to empower future studies of cell-to-cell communication, secreted protein function, and biomarker discovery for any given cell type in vitro or in vivo.