TGF-β/Smad相关的上皮-成纤维细胞重塑是慢性鼻窦炎伴鼻息肉中胶原沉积的基础

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中文摘要

背景： 慢性鼻窦炎伴鼻息肉（CRSwNP）常伴有上皮屏障破坏和组织重塑。本研究旨在探讨在CRSwNP鼻黏膜重塑过程中，上皮-间质转化（EMT）、成纤维细胞活化、胶原沉积和TGF-β/Smad信号传导是否协同发生。
材料与方法： 整合来自两个独立人类队列的公开单细胞RNA测序数据集，以表征上皮细胞、成纤维细胞和髓系细胞的异质性、疾病相关转录变化、拟时序动态和细胞间通讯，并应用CellChat分析COLLAGEN和TGF-β信号模块。对CRSwNP患者的鼻息肉和对照鼻黏膜进行免疫荧光、Masson三色染色和高碘酸-希夫（PAS）染色。使用卵清蛋白（OVA）/金黄色葡萄球菌肠毒素B（SEB）诱导的CRSwNP样小鼠模型，包括地塞米松干预组，进行组织病理学、免疫荧光和Western blot验证。
结果： 在CRSwNP中，成纤维细胞向活化的基质重塑状态转变，上皮细胞表现出增强的损伤修复和EMT相关特征，而TGFB1优先在息肉中扩增的GPNMB表达巨噬细胞亚群中检测到。潜在的上皮-成纤维细胞通讯在COLLAGEN和TGF-β模块中富集，TGFB1-TGFBR1/TGFBR2和COL1A1-SDC4/CD44成为候选配体-受体对。人类息肉显示胶原沉积、α-SMA高表达成纤维细胞富集、EMT样上皮改变和核内p-Smad3积累。小鼠模型重现了这种模式，地塞米松在蛋白质水平部分逆转了该模式。
讨论： 通过整合人类单细胞转录组学与组织和蛋白质水平验证，本研究表征了一个协调的、TGF-β/Smad3相关的上皮-成纤维细胞重塑程序，该程序是CRSwNP中胶原沉积的基础。这些候选轴，连同TGFB1的巨噬细胞来源，为上皮-成纤维细胞-免疫串扰提供了机制线索；地塞米松的部分可逆性支持通路靶向抗重塑策略，而其因果作用尚待空间和功能验证。

英文摘要

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is frequently accompanied by epithelial barrier disruption and tissue remodeling. This study aimed to investigate whether epithelial-mesenchymal transition (EMT), fibroblast activation, collagen deposition, and TGF-β/Smad signaling are coordinated during CRSwNP nasal mucosal remodeling.
MATERIALS AND METHODS: Publicly available single-cell RNA sequencing datasets from two independent human cohorts were integrated to characterize epithelial, fibroblast, and myeloid heterogeneity, disease-associated transcriptional changes, pseudotime dynamics, and cell-cell communication, with CellChat applied to the COLLAGEN and TGF-β signaling modules. Immunofluorescence, Masson's trichrome, and periodic acid-Schiff (PAS) staining were performed on nasal polyps from CRSwNP patients and control nasal mucosa. An ovalbumin (OVA)/Staphylococcus aureus enterotoxin B (SEB)-induced CRSwNP-like mouse model, including a dexamethasone intervention arm, was used for histopathological, immunofluorescence, and Western blot validation.
RESULTS: In CRSwNP, fibroblasts shifted toward activated, matrix-remodeling states, and epithelial cells displayed enhanced injury-repair and EMT-related features, while TGFB1 was preferentially detected in a GPNMB-expressing macrophage subset expanded in polyps. Potential epithelial-fibroblast communication was enriched within COLLAGEN and TGF-β modules, with TGFB1-TGFBR1/TGFBR2 and COL1A1-SDC4/CD44 emerging as candidate ligand-receptor pairs. Human polyps showed collagen deposition, α-SMA-high fibroblast enrichment, EMT-like epithelial changes, and nuclear p-Smad3 accumulation. The mouse model recapitulated this pattern, and dexamethasone partially reversed it at the protein level.
DISCUSSION: Integrating human single-cell transcriptomics with tissue- and protein-level validation, this study characterizes a coordinated, TGF-β/Smad3-associated epithelial-fibroblast remodeling program underlying collagen deposition in CRSwNP. These candidate axes, together with a macrophage source of TGFB1, offer mechanistic clues to epithelial-fibroblast-immune crosstalk; their partial reversibility by dexamethasone supports pathway-targeted anti-remodeling strategies, while causal roles await spatial and functional validation.