Extracellular Vesicles from patients with Antibody-Mediated Rejection induce tubular senescence and endothelial to mesenchymal transition by regulating complement activation through horizontal transfer of miRNAs

Extracellular vesicles (EV) has been shown to deliver potential microRNA (miRNA) as cargo for specific target cells; effectively, the EV unique nature of the bilayer allows miRNA to be protected from degradation. We used microarray analysis to compare the miRNA profiles of EV isolated from acute antibody-mediated allograft rejection patients (AAMR) and chronic antibody-mediated allograft rejection (CAMR) compared to Tx Controls patients. By microarray miRNA profiling we detected 42 miRNAs downregulated and 34 miRNAs upregulated with FDR < 0.05 and Fold change >2. Principal Component analysis showed that these 76 miRNAs were able to distinguish AMR-derived EV from healthy TX patients. We also investigated whether differences in EV miRNA content could separate AAMR and CAMR patients. We found 9 miRNAs differentially expressed in the two AMR groups (eight downregulated and only one upregulated in AAMR compared to CAMR; effectively, these miRNAs could distinguish AAMR-derived EV from CAMR-derived EV. We then investigated the possible target genes of these miRNAs according to their expression, fold change and the p value; interestingly, several targets were associated to CDKN1A and CDKN2A genes regulation.