Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate IMQ-Induced Psoriasiform Dermatitis: A Preclinical Experimental Study of Exosomal miR-125b-5p/STAT3 Signaling.

Background and Aims: Psoriasis is a chronic inflammatory skin disease driven largely by dysregulation of the IL-23/Th17 axis and excessive keratinocyte proliferation. Human umbilical cord mesenchymal stem cell (MSC)-derived exosomes (hucMSC-Exos) represent a potential cell-free therapeutic strategy, but their mechanisms remain incompletely defined. This study evaluated the effects of hucMSC-Exos in psoriasiform inflammation and investigated the contribution of exosomal miR-125b-5p and its relationship with STAT3 signaling. Methods: hucMSC-Exos were isolated by differential ultracentrifugation and characterized by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and immunoblotting. Therapeutic effects were assessed in an imiquimod (IMQ)-induced mouse model of psoriasiform dermatitis using PASI-like scoring, histopathology, immunohistochemistry, flow cytometry, and western blotting. Exosomal microRNAs (miRNAs) were profiled by high-throughput sequencing. STAT3 targeting was examined by dual-luciferase reporter assays, and the functional contribution of miR-125b-5p was assessed using exosomes loaded with a miR-125b-5p inhibitory oligonucleotide and negative-control exosomes (NC-Exos). Results: hucMSC-Exos alleviated IMQ-induced psoriasiform dermatitis, as reflected by reduced epidermal hyperplasia and fewer Ki-67-positive keratinocytes. Exosome treatment was associated with decreased phosphorylation of STAT3 and JNK, lower IL-23 and IL-17A expression, decreased Th17-cell frequency, and increased regulatory T cell (Treg)-cell frequency. In vitro, hucMSC-Exos suppressed Th17-cell proliferation while promoting Treg-cell expansion. miR-125b-5p was among the abundant miRNAs detected in hucMSC-Exos, and dual-luciferase reporter assays supported STAT3 as a direct target of miR-125b-5p. Compared with NC-Exos, inhibitor-loaded exosomes (IN-Exos) were less effective at alleviating IMQ-induced psoriasiform dermatitis; this reduced efficacy was accompanied by increased STAT3 and JNK phosphorylation, higher IL-23 and IL-17A expression, a higher Th17-cell frequency, and a lower Treg-cell frequency. Conclusion: hucMSC-Exos attenuated psoriasiform inflammation and were associated with reduced inflammatory signaling, decreased Th17-cell frequency, and increased Treg-cell frequency. Our findings further suggest that exosomal miR-125b-5p contributes, at least in part, to these effects through direct regulation of STAT3.