Variability in the levels of exosomal miRNAs among human subjects could be explained by differential interactions of exosomes with the endothelium

Abstract

Exosomes are 30–100 nm endosome‐derived membrane vesicles, that contain specific RNA transcripts including mRNAs, and microRNAs (miRNAs) and have been implicated in cell‐to‐cell communication. Exosomal miRNAs in blood circulation have been attracting major interest as potential diagnostic and prognostic biomarkers in a variety of diseases including stroke, cancer, and inflammatory disorders. Despite the progress made in the utilization of circulating exosomal miRNAs as biomarkers for various human diseases and conditions, there are still difficulties in functionally utilizing such methods in the clinic due to the high variability observed among subjects. Attempts to use miRNA signatures have improved but have not eliminated the problem. Additionally, standardized laboratory practices may partially reduce variability but there is still an unknown biological factor that hinders the proper use of miRNAs as biomarkers. We hypothesize that this variability might be partially attributed to a differential interaction among circulating exosomes carrying those miRNAs with endothelial surface molecules that themselves may vary among individuals due to secondary conditions, for example, inflammation status. This differential interaction could potentially add variability to the level of the examined miRNA that is not directly attributed to the primary condition under study.

Exosomal miRNAs as Biomarkers of Ischemic Stroke

“…Significant limitations to introducing exosomal miRNA in real-world clinical practice must be mentioned. First, the methods to isolate exosomes are quite complex, and, to date, there is no standardization, making it difficult to compare and reproduce results, as also assessed by the high heterogeneity among studies [91]. It is critical to ensure standardized and reproducible methods for clinical translation.…”

The Circulating Biomarkers League: Combining miRNAs with Cell-Free DNAs and Proteins

“…Recently, we suggested that the differences in exosomal miRNA levels between patient samples and those from healthy individuals could stem from how exosomes containing c-miRNAs interact with endothelial receptors. These receptors tend to be more prevalent in states of disease, such as inflammation [ 154 ].…”

Exploring the Feasibility of Circulating miRNAs as Diagnostic and Prognostic Biomarkers in Osteoarthritis: Challenges and Opportunities

“…Recently, we proposed that the observed variability in exosomal miRNA levels in patient samples compared to healthy individuals might be partly due to interactions between exosomes carrying c-miRNAs and endothelial receptors. These receptors are often overexpressed under pathological conditions such as inflammation [153].…”

“…Despite efforts to compare and optimize these methods, interlaboratory differences persist across isolation methods, yielding varied miRNA quantities and qualities (reviewed in [153]). For example, studies have found that TRIzol-based methods negatively impact RNA quality and that column-based methods are preferred.…”