人脐带间充质干细胞来源的外泌体可减轻IMQ诱导的银屑病样皮炎：外泌体miR-125b-5p/STAT3信号通路的临床前实验研究

Abstract

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 accomp