MicroRNA-100-5p in exosomes from human placental mesenchymal stem cells: a key modulator of anti-psoriatic effects through mTOR/S6 K1 pathway.

Exosomes from mesenchymal stem cells (MSCs) demonstrate therapeutic potential against psoriasis, primarily due to their anti-inflammatory properties. However, the specific components within the exosomal cargo, particularly microRNAs, that mediate this activity remain unclear. This study investigated the role of a specific microRNA in mediating the therapeutic effects of exosomes from human placenta MSCs (MSC-exosomes) in an imiquimod (IMQ)-induced psoriasis murine model, with a focus on the underlying mechanisms, particularly the downstream pathways of the specific microRNA. Our small RNA sequencing analysis identified microRNA (miR)-100-5p as a potential target. Adult male Balb/c mice were then randomly assigned to the IMQ, IMQ plus MSC-exosomes (IMQ + Exo), IMQ plus MSC-exosomes treated with a specific miR-100-5p inhibitor (IMQ + Exoi), or IMQ plus agomiR-100-5p group (IMQ + AgomiR) (n = 6 per group). Control groups were also included. Mice were sacrificed, and psoriasis severity was assessed the day after 6 consecutive days of daily IMQ exposure, followed by 7 consecutive days of daily treatment. The IMQ + Exo group exhibited significantly lower epidermal thickness, levels of inflammatory cytokines and psoriasis-related cytokines (interleukin [IL]-12, IL-17, and IL-23), and expression of mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) (the predicted downstream target of miR-100-5p), compared to the IMQ group (all p < 0.05). Notably, inhibition of miR-100-5p nullified these therapeutic effects of MSC-exosomes. This study provides evidence that miR-100-5p plays a crucial role in mediating the therapeutic effects of MSC-exosomes in an IMQ-induced murine psoriasis model, potentially by modulating the mTOR/S6K1 pathway. KEY MESSAGES: • Exosomes from human placental mesenchymal stem sells demonstrate therapeutic potential against psoriasis. • MicroRNA-100-5p plays a crucial role in mediating the therapeutic effects of mesenchymal stem cells exosomes in an imiquimod-induced murine psoriasis  model, potentially by modulating the mammalian target of rapamycin/S6 kinase 1 pathway.