(T1089) SMALL EXTRACELLULAR VESICLES FROM METABOLICALLY REPROGRAMMED MESENCHYMAL STEM/STROMAL CELL AS A POTENTIAL IMMUNOSUPPRESSIVE MECHANISM FOR INFLAMMATORY AND AUTOIMMUNE DISEASES
PhDc Universidad de los Andes/IMPACT santiago, Region Metropolitana, Chile
Abstract: Inflammatory and autoimmune diseases significantly impact patients' health and quality of life, and their treatment remains a clinical challenge. Mesenchymal stem cells (MSCs), with diverse biological functions, represent a promising therapeutic approach due to their immunoregulatory effects. The immunomodulatory activity of MSCs is primarily mediated by paracrine factors. However, small extracellular vesicles (sEVs) have been identified as key players in mediating MSCs' biological functions. Our studies on human umbilical cord MSCs (UC-MSCs) demonstrated that metabolic reprogramming to glycolysis significantly enhances their immunoregulatory capacity, particularly in modulating proinflammatory T cells (Th1, Th17) and inducing regulatory T cells (Tregs). In this study, we evaluated the immunosuppressive properties of sEVs derived from glycolytic and non-glycolytic UC-MSCs both in vitro and in vivo.
sEVs-MSCglyco and sEVs-MSCnon-glyco were isolated and characterized using NTA and FACS. Their immunosuppressive activity was assessed first on PBMCs. Additionally, sEV internalization by T cells was evaluated using RTqPCR. We also analyzed the effect of sEVs on memory T cells by FACS, and the production of IL-10, measured by ELISA. Finally, we investigated the immunosuppressive activity of sEVs in vivo using mouse models of delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA).
sEVs-MSCglyco significantly reduced T cell proliferation, decreased Th1 cell populations, and induced Treg cells in vitro. Additionally, sEVs were internalized by memory T cells, leading to a reduction in Th1 and Th17 cell populations without affecting Tregs, alongside an increase in IL-10 production. In vivo, sEVs-MSCglyco significantly reduced the inflammatory response in the DTH model by decreasing proinflammatory T cell populations. In the CIA model, infusion of sEVs-MSCglyco reduced disease incidence and progression compared to the control group, correlating with a significant decrease in Th1 and Th17 cells in lymph nodes and peripheral blood.
Glycolytic MSC-derived sEVs effectively modulate activated T cells, enhancing immunoregulatory capabilities both in vitro and in vivo, underscoring their potential as a therapeutic tool for treating inflammatory and autoimmune diseases.
Funding Source: Supported by the ANID from Chile through the grants FONDECYT Regular N°1211353; FONDEF ID: 21110194; and IMPACT FB 210024; Fondecyt Inicio: 11220549; Beca Doctorado Nacional Folio:21210735 and beca FAI Universidad de los Andes.
