Glycolytic MSC-derived EVs restrain arthritis progression by promoting IL-10-producing T and B cells

Current treatments for autoimmune diseases like arthritis often fall short due to systemic side effects or insufficient efficacy in resolving chronic inflammation. Mesenchymal stromal cells (MSCs) and their secreted extracellular vesicles (EVs) offer a promising cell-free immunomodulatory approach. However, enhancing their therapeutic potency remains a key challenge. This study investigates whether glycolytic reprogramming, known to boost MSC immunosuppression, translates to their EVs, specifically targeting the IL-10 pathway and regulatory T/B cell responses to address the inflammatory gap in arthritis.

Researchers isolated and characterized EVs from both naïve and glycolytically reprogrammed human umbilical cord-derived MSCs (EVs-UC-MSCnaive and EVs-UC-MSCglyco). They then compared their effects on memory CD4+ T and B cells in vitro. For in vivo efficacy, the EVs were tested in two murine models: the delayed-type hypersensitivity (DTH) model for acute inflammation and the collagen-induced arthritis (CIA) model for chronic autoimmune arthritis. The study assessed inflammation, arthritis incidence, clinical severity, and immune cell ratios, alongside microRNA profiling to identify key regulatory elements.

In vitro, EVs-UC-MSCglyco more effectively suppressed inflammatory T cell responses and promoted IL-10-producing Tr1 and B cells compared to EVs-UC-MSCnaive. They also enhanced B cell survival. In vivo, the therapeutic potential was evident: > EVs-UC-MSCglyco significantly reduced inflammation in the DTH murine model and decreased both arthritis incidence and clinical severity in the CIA model. These beneficial effects were strongly associated with increased Treg/Th1, Treg/Th17, Tr1/Th1, and Tr1/Th17 ratios, alongside enhanced IL-10 production. MicroRNA profiling revealed an enrichment of regulatory miRNAs in EVs-UC-MSCglyco, notably miR-365a-5p, which is linked to the suppression of pro-inflammatory signaling and activation of the IL-10 regulatory axis, providing a mechanistic insight into their enhanced immunomodulatory capacity.