Abstract
Background: The transplantation of pancreatic islets is a promising strategy for restoring insulin production in patients with Type 1 Diabetes (T1D). However, immune-mediated rejection of transplanted islets remains a major challenge, necessitating chronic systemic immunosuppression, which has significant risks. Mesenchymal Stem Cells (MSCs) and their extracellular vesicles (EVs), including exosomes, possess immunomodulatory properties. MSC-derived exosomes and EVs could be harnessed to mitigate immune-mediated damage and protect insulin-producing islet β-cells.
This study aims to evaluate the effects of human Umbilical Cord-derived MSC (UC-MSC) exosomes and EVs on human pancreatic islets and immune cells, with a particular focus on their ability to suppress inflammation and preserve β-cell function.
Methodology: Exosomes and EVs were generated by culturing clinical-grade UC-MSCs in a cGMP-grade medium prepared at the Diabetes Research Institute's cGMP facility, following a standardized culture strategy. Exosomes and EVs were isolated and characterized. Their effects were tested in in vitro cultures with activated T cells, macrophages, islets, and in a human islet immune attack model. The effect of exosome treatment was assessed using flow cytometry for markers of activated T cells and regulatory T cells (Tregs), gene expression profiling for macrophage polarization, and glucose-stimulated insulin release (GSIR) assays to evaluate β-cell function.
Results: UC-MSC-derived exosomes suppressed islet inflammation, induced exhaustion of cytotoxic CD8+ T cells, and promoted the expansion of Tregs and M2-like macrophages, leading to an immunoregulatory shift that favored islet survival. Exosome treatment preserved β-cell insulin secretion under inflammatory conditions and counteracted the deleterious effects of activated T cells on β-cells, thereby maintaining β-cell function. These findings suggest that UC-MSC-derived exosomes and EVs can inhibit islet inflammation, modulate immune attacks against islet cells, and protect β-cell function.
Conclusions: This study indicates that UC-MSC-derived exosomes and EVs exert potent immunomodulatory effects, reducing islet inflammation and preserving β-cell function. These findings support the potential of exosomes and EVs as an adjuvant strategy for islet cell transplantation, with the goal of reducing immune-mediated rejection and minimizing the need for systemic immunosuppression in islet transplantation for T1D.