Bone Marrow Mesenchymal Stem Cells-Derived miR-21-5p Protects Grafted Islets Against Apoptosis by Targeting PDCD4

We demonstrated that BMSCs could deliver exosomes containing miR-21-5p into islet cells.Then, we found that miR-21-5p overexpression attenuated apoptosis of islets and rat insulinoma (INS-1) cells, while miR-21-5p inhibition significantly promoted apoptosis.The upregulated miR-21-5p directly binds to the 3'UTR of PDCD4, thereby reducing apoptosis in transplanted islets. This study confirms the results of previous studies, suggesting that miR-21-5p can be used as a therapeutic agent to minimize beta-cell apoptosis in the early stage of islet transplantation and thus improve the transplantation outcome. The apoptosis of grafted islets is an urgent problem due to the high rate of islet loss soon after transplantation. MicroRNA-21-5p (miR-21-5p) is an essential mediator of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exo) during anti-apoptosis, but its effect and the underlying molecular mechanism in islet transplantation remain partially understood. Here, we found that miR-21-5p could be delivered to islet cells via BMSCs-Exo. Subsequently, we demonstrated that miR-21-5p overexpression reduced apoptosis in islets and INS-1 cells, whereas miR-21-5p inhibition enhanced apoptosis. A mechanistic analysis involving RNA sequencing and bioinformatic analysis was performed to determine the interaction between miR-21-5p and its target gene programmed cell death 4 (PDCD4), which was further verified by a dual luciferase assay. In vivo, the grafted islets overexpressing miR-21-5p showed a higher survival rate, better insulin secretion function, and a lower apoptosis rate. In conclusion, these results demonstrated that miR-21-5p from BMSCs-Exo protects against the apoptosis of grafted islets by inhibiting PDCD4 expression. Hence, miR-21-5p can be used as a cell-free therapeutic agent to minimize beta-cell apoptosis at the early stage of islet transplantation.