Background and aims: Type 1 diabetes (T1D) involves autoimmune destruction of insulin-producing cells. Targeting immune cells has shown promise in T1D, implying the importance of immunomodulatory molecules. We assessed human islet-derived progenitor cells (hIPCs), which share several characteristics with mesenchymal stem cells, for their immunomodulatory potential.
Methods: Human islet-derived cells (hIPCs) were generated following epithelial-to-mesenchymal transition of human cadaveric islets. These hIPCs were then co-cultured with phytohemagglutinin stimulated human peripheral blood mononuclear cells (PBMCs) and their proliferation was assessed using flow cytometry. We also tested the effect of co-culture supernatant (CCS) and isolated extracellular vesicles (EVs) on PBMC proliferation. Proteomic (LC-MS/MS and Olink) and transcriptomic (miRNA) workflows were aimed to identify regulatory molecules.
Results: We observed 80-90% proliferation inhibition (p<0.001) of various immune cell subsets (CD4+ T, CD8+ T, CD19+ B) in a direct (cell-to-cell) or indirect (transwell) co-culture with hIPCs. When EV inhibitors were used in co-culture, hIPCs lost their ability to inhibit PBMC proliferation, suggesting the role of EVs in immunomodulation. EVs isolated from CCS (126.2+21.9 nm in size) inhibited CD4+ T-cell proliferation (70% reduction, p<0.01) when added directly to stimulated PBMCs at a concentration of 1.3x109 particles. Interestingly, EVs isolated from hIPC supernatant (controls) had an average size of 108.94+11.70 nm, and did not inhibit CD4+ T-cell proliferation (0-5% inhibition, not significant).
Discussion: Human islet-derived cells, co-culture supernatant and CCS-EVs exhibit immunomodulatory properties, presenting potential new treatments for T1D. Current work using transcriptomics and proteomics will provide detailed characterization of culture supernatants and EVs.