Tissue differences in the exosomal/small extracellular vesicle proteome and their potential as indicators of altered tissue metabolism.

Exosomes/small extracellular vesicles (sEVs) can serve as multifactorial mediators of cell-to-cell communication through their miRNA and protein cargo. Quantitative proteomic analysis of five cell lines representing metabolically important tissues reveals that each cell type has a unique sEV proteome. While classical sEV markers such as CD9/CD63/CD81 vary markedly in abundance, we identify six sEV markers (ENO1, GPI, HSPA5, YWHAB, CSF1R, and CNTN1) that are similarly abundant in sEVs of all cell types. In addition, each cell type has specific sEV markers. Using fat-specific Dicer-knockout mice with decreased white adipose tissue and increased brown adipose tissue, we show that these cell-type-specific markers can predict the changing origin of the serum sEVs. These results provide a valuable resource for understanding the sEV proteome of the cells and tissues important in metabolic homeostasis, identify unique sEV markers, and demonstrate how these markers can help in predicting the tissue of origin of serum sEVs.