EV-origin: Enumerating the tissue-cellular origin of circulating extracellular vesicles using exLR profile

Abstract Extracellular vesicles (EVs) are complex ecosystems that can be derived from all body cells and circulated in the body fluids. Characterizing the tissue-cellular source contributing to circulating EVs provides biological information about the cell or tissue of origin and their functional states. However, the relative proportion of tissue-cellular origin of circulating EVs in body fluid has not been thoroughly characterized. Here, we developed an approach for digital EVs quantification, called EV-origin, that enables enumerating of EVs tissue-cellular source contribution from plasma extracellular vesicles long RNA sequencing profiles. EV-origin was constructed by the input matrix of gene expression signatures and robust deconvolution algorithm, collectively used to separate the relative proportions of each tissue or cell type of interest. EV-origin respectively predicted the relative enrichment of seven types of hemopoietic cells and sixteen solid tissue subsets from exLR-seq profile. Using the EV-origin approach, we depicted an integrated landscape of the traceability system of plasma EVs for healthy individuals. We also compared the heterogenous tissue-cellular source components from plasma EVs samples with diverse disease status. Notably, the aberrant liver fraction could reflect the development and progression of hepatic disease. The liver fraction could also serve as a diagnostic indicator and effectively separate HCC patients from normal individuals. The EV-origin provides an approach to decipher the complex heterogeneity of tissue-cellular origin in circulating EVs. Our approach could inform the development of exLR-based applications for liquid biopsy.