Quality Management Tools on the Stage: Old but New Allies for Rigor and Standardization of Extracellular Vesicle Studies

As early as the second half of the 19th century, Charles Darwin hypothesized as a part of his pangenesis theory that every cell type in the body could generate minute size "gemmules" full of molecules to communicate with other cell types (Darwin, 1868). This seminal intuition fell unnoticed for more than 150 years until contemporary scientists may recognize extracellular vesicles (EVs) in Darwin's gemmules (Liu and Chen, 2018; Margolis and Sadovsky, 2019; Bergese et al., 2020). Nowadays it has been clearly shown that cells from different organisms, including eukaryotes, both animals (from yeast to mammals) and plants, but also prokaryotic cells, have been demonstrated to release vesicles into the extracellular environment either constitutively or following cell stimulation. EVs have also been isolated from diverse body fluids, including blood, urine, saliva, breast milk, amniotic fluid, cerebrospinal fluid, bile, and semen (Keller et al., 2011; Kalluri and LeBleu, 2020). All EVs are lipid-membrane encapsulated particles filled of cellular content, comprising proteins, metabolites, nucleic acids, lipids, and even entire organelles, some of them specifically sorted and enriched in EV populations with a pattern reflective of cell functions and conditions (Raposo and Stoorvogel, 2013; Yáñez-Mó et al., 2015; Meldolesi, 2018; Van Niel et al., 2018). Very far from representing a tool to eliminate waste material, as hypothesized at the beginning, EVs are able to target specific cells and deliver molecules that induce specific cell response (Van Niel et al., 2018; Kalluri and LeBleu, 2020; Mantile et al., 2020). Therefore, EV-based cell communication has become an extremely intriguing mechanism that attracted a lot of scientists for its great potential in basic as well as applied research.