Bone marrow mesenchymal stem cells-derived miR-21-5p protects grafted islets against apoptosis by targeting PDCD4

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 β-cell Apoptosis at the early stage of islet transplantation.

PDCD4; apoptosis; bone marrow mesenchymal stem cells; exosomes; islet transplantation; miR-21-5p.