间充质干细胞来源的小细胞外囊泡重新平衡Th2/Th17反应并减轻嗜酸性慢性鼻窦炎中的上皮重塑
Mesenchymal stem cell-derived small extracellular vesicles rebalance Th2/Th17 responses and attenuate epithelial remodeling in eosinophilic chronic rhinosinusitis.
文献信息
| PMID | 42849120 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Boyu Cai |
| 作者单位 | Department of ORL-HNS, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China; Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai 200070, China. |
| 期刊 | International immunopharmacology |
| SCI 分区 | Q1 |
| IF | 5.7 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 鼻科 |
中文摘要
嗜酸性慢性鼻窦炎（ECRS）是一种难治性亚型，以Th2炎症占优势和进行性组织重塑为特征，术后复发率高且当前生物制剂疗效有限。间充质干细胞来源的小细胞外囊泡（MSC-sEV）代表一种有前景的无细胞纳米治疗策略，但其在ECRS中的疗效仍研究不足。本研究在木瓜蛋白酶诱导的ECRS模型中探讨了鼻内MSC-sEV对Th2/Th17免疫失调和黏膜重塑的治疗效果。在激发期鼻内给予MSC-sEV显著减轻了临床症状并减轻了关键病理特征，包括上皮增生、杯状细胞增生、黏液分泌过多和黏膜嗜酸性粒细胞浸润，后者通过H&E染色切片上直接嗜酸性粒细胞定量得到证实。免疫组织化学显示，MSC-sEV通过下调FXIII-A和CLCA1等标志物并部分恢复E-cadherin水平来减轻气道重塑，表明EMT样改变减弱。脾淋巴细胞的流式细胞术显示，MSC-sEV部分恢复了紊乱的全身Th1/Th2/Th17平衡，对Th17相关反应的影响更为明显，而GATA3、IL-17 A和TNF-α的免疫组织化学证实了鼻黏膜中一致的变化。转录组分析显示，这些治疗效果与嗜酸性粒细胞募集趋化因子（Ccl11、Ccl24）的下调以及IL-17、TNF和JAK-STAT信号富集减少相关——在蛋白质水平上通过STAT3和NF-κB p65磷酸化降低以及RT-qPCR确认九个关键转录本得到佐证。总之，本研究确定MSC-sEV是一种有效的无细胞策略，通过部分恢复免疫稳态和减轻上皮重塑来减轻ECRS的发展。
英文摘要
Eosinophilic chronic rhinosinusitis (ECRS) is a refractory subtype characterized by dominant Th2 inflammation and progressive tissue remodeling, with high postoperative recurrence and limited efficacy of current biological agents. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) represent a promising cell-free nanotherapeutic approach, yet their efficacy in ECRS remains poorly studied. This study investigated the therapeutic efficacy of intranasal MSC-sEV against Th2/Th17 immune dysregulation and mucosal remodeling in a papain-induced ECRS model. Intranasal administration of MSC-sEV during the challenge phase significantly alleviated clinical symptoms and attenuated key pathological features, including epithelial hyperplasia, goblet cell hyperplasia, excessive mucus secretion and mucosal eosinophil infiltration, the latter confirmed by direct eosinophil quantification on H&E-stained sections. Immunohistochemistry showed that MSC-sEV attenuated airway remodeling by downregulating markers such as FXIII-A and CLCA1 while partially restoring E-cadherin levels, indicating attenuation of EMT-like changes. Flow cytometry of splenic lymphocytes revealed that MSC-sEV partially restored the disturbed systemic Th1/Th2/Th17 balance, with a more evident effect on the Th17-associated response, and immunohistochemistry for GATA3, IL-17 A and TNF-α confirmed concordant changes in the nasal mucosa. Transcriptomic analysis showed that these therapeutic effects were associated with downregulation of eosinophil-recruitment chemokines (Ccl11, Ccl24) and with reduced enrichment of IL-17, TNF and JAK-STAT signaling-corroborated at the protein level by decreased phosphorylation of STAT3 and NF-κB p65 and by RT-qPCR confirmation of nine key transcripts. Collectively, this study identifies MSC-sEV as an effective cell-free strategy that attenuates the development of ECRS by partially restoring immune homeostasis and attenuating epithelial remodeling.