Abstract：
Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (MSC-sEV) provide a pragmatic solution as a cell-free therapy for patients with diabetic kidney disease (DKD). However, the underlying protective mechanisms of MSC-sEV remain largely unknown in DKD. Invivo and in vitro analyses demonstrated that MSC-sEV attenuated renal fibrosis and inflammation of DKD. The underlying mechanism of the MSC-sEV-induced therapeutic effect was explored by high-throughput sequencing, which identified the unique enrichment of a set of miRNAs in MSC-sEV compared with human skin fibroblasts-sEV (HSF-sEV). Vitro experiments demonstrated that the protective potential was primarily attributed to miR-23a-3p, one of the most abundant miRNAs in MSC-sEV. Further, overexpression or knockdown analyses revealed that miR-23a-3p, and its target Krüppel-like factor 3 (KLF3) suppressed the STAT3 signaling pathway in high glucose (HG) induced HK-2 cells were essential for the renal-protective property of MSC-sEV. Moreover, we found that miR-23a-3p was packaged into MSC-sEV by RNA Binding Motif Protein X-Linked (RBMX) and transmitted to HG-induced HK-2 cells. Finally, inhibiting miR-23a-3p could mitigate the protective effects of MSC-sEV in db/db mice. These findings suggest that a systemic administration of sEV derived from MSC, have the capacity to incorporate into kidney where they can exert renal-protective potential against HG-induced injury through delivery of miR-23a-3p.
摘要：
人脐带间充质干细胞来源的小细胞外囊泡（MSC-sEV）为糖尿病肾病（DKD）患者的无细胞治疗提供了实用的解决方案。然而,在DKD中,MSC-sEV的潜在保护机制仍然未知.体内和体外分析表明，MSC-sEV减轻了DKD的肾脏纤维化和炎症。通过高通量测序探索MSC-sEV诱导治疗效果的潜在机制，其鉴定了与人皮肤成纤维细胞-sEV(HSF-sEV)相比MSC-sEV中一组miRNA的独特富集。体外实验表明，保护潜力主要归因于miR-23a-3p，MSC-sEV中最丰富的miRNA之一。Further,过表达或敲低分析显示miR-23a-3p，其靶标Krüppel样因子3（KLF3）抑制了高糖（HG）诱导的HK-2细胞中的STAT3信号通路，这对于MSC-sEV的肾脏保护特性至关重要。此外，我们发现miR-23a-3p通过RNA结合基序蛋白X连接(RBMX)包装到MSC-sEV中,并传递至HG诱导的HK-2细胞。最后,抑制miR-23a-3p可以减轻db/db小鼠MSC-sEV的保护作用。这些发现表明，系统性给予源自MSC的sEV，具有整合到肾脏中的能力，在那里它们可以通过递送miR-23a-3p来发挥针对HG诱导的损伤的肾脏保护潜力。
