Extracellular vesicles derived from clonal mesenchymal stromal cells preconditioned by indirect hypoxia modulate immune responses in diabetic mice more effectively than directly preconditioned vesicles

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Background Mesenchymal stem/stromal cells (MSCs) or MSC-derived extracellular vesicles (MSC-EVs) are considered potential modulators of the immune system in type 1 diabetes (T1D) therapy. On the other hand, preconditioning MSCs with inflammatory agents is a promising strategy to improve the therapeutic effects of these cells. Therefore, we performed various direct preconditioning regimens (IFN-γ, poly(I: C), LPS, and hypoxia) on clonal MSCs (cMSCs), and for indirect preconditioning regimens, the same regimens were applied to peripheral blood mononuclear cells (PBMCs). PBMC-derived concentrated conditioned media (CCM) was transferred into cMSC cultures to mimic in vivo conditions to obtain cMSC-EVs with better immunomodulatory effects and then selected hypoxia-induced cMSC-EVs and their source cells to determine their influence on immune responses in multiple low-dose/Streptozotocin (MLD/STZ)-induced mouse model. Methods Direct preconditioning regimens include four groups: IFN-γ (50 ng/ml), poly(I: C) (42.22 µg/ml), LPS (1 µg/ml), and hypoxia (1% oxygen). For indirect preconditioning, these regimens were applied to PBMCs, and PBMC-derived CCM was added to cMSC cultures. The resulting cMSC-CCM was assessed for the expression of anti-inflammatory, pro-inflammatory, and regenerative factors and its ability to inhibit lymphocyte proliferation. The isolated EVs from the most effectiv

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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