Regulation of Immune Cell Proliferation by microRNAs

Transplantation of cadaveric islets is currently the only clinically recognized cell therapy for treatment of type 1 diabetes. Long-term success of this therapy is severely limited by multiple factors, including the immune-mediated destruction of transplanted islets. Development of molecular immunosuppressive strategies could offer much efficient graft survival thereby improving graft function and quality of life. Here we demonstrate that one of the novel mechanisms of immune regulation involves inter-cellular transfer of microRNAs via exosomes.

We have established and extensively characterized human islet-derived progenitor cells (hIPCs), which are generated following epithelial-to-mesenchymal transition (EMT) and proliferation (expansion) of human cadaveric islet cells. Initial characterization of hIPCs indicates that they exhibit most of the characteristics of mesenchymal stem cells, including expression of CD73, CD90 and CD105. We observed that hIPCs can significantly inhibit (>90%) in vitro proliferation of different immune cell subsets (CD4+ T, CD8+ T, CD19+ B) of (PHA)-stimulated PBMCs in a co-culture system. RNA-sequencing and validation studies pointed to a potential role of microRNAs in inhibition of T cell proliferation. Recently, microRNAs have been demonstrated to shuttle between cells and are reported to be involved in inter-cellular gene regulation. When microRNAs were analysed in hIPCs alone and in hIPCs co-cultured with PBMCs, we found a small subset of significantly altered microRNAs. These microRNAs showed increase in abundance in PBMCs from co-culture setting and were higher in co-culture supernatant. When exosomal inhibitors were used to prevent the transfer of microRNAs from hIPCs in a co-culture setting, we found that T-cell proliferation was rescued back to normal.

We believe that this study could help in discovering novel immunoregulatory molecules that may have a potential role for improving graft survival in islet transplantation for type 1 diabetes.