Liang Xiuping, Li Yanhong, Wu Yinlan, Wu Tong, Huang Deying, Tang Ziyi, Cheng Lu, Tan Chunyu, Liao Ronghui, Zhao Jing, Liao Zehui, Luo Yubin, Liu Yi
Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
Stem Cell Res Ther. 2025 Mar 24;16(1):145. doi: 10.1186/s13287-025-04266-w.
Pulmonary fibrosis (PF) is a disease with high morbidity and mortality rates, but effective treatment options are extremely limited. Mesenchymal stem cells (MSCs) and their derivatives show promise as potential therapeutics for PF. However, the underlying mechanisms responsible for these beneficial effects remain poorly understood. The objective of this study was to elucidate the specific mechanism through which microvesicles derived from human umbilical cord MSCs (MSC-MVs) alleviate PF.
The effects of MSC-MVs on PF in bleomycin (BLM)-induced mice were assessed via histological staining, flow cytometry, and enzyme-linked immunosorbent assays (ELISAs). The potential therapeutic target was identified via RNA sequencing (RNA-seq) analysis, followed by validation via real-time quantitative polymerase chain reaction (RT‒qPCR), ELISAs, scratch testing, and western blotting (WB).
MSC-MVs significantly attenuated collagen fiber deposition and downregulated the expression of extracellular matrix components in the lungs of the BLM-induced mice. Moreover, this treatment substantially ameliorated lung inflammation by reducing the monocyte‒macrophage ratio and the TNF-α and IL-6 levels. Further analyses revealed that MSC-MVs inhibited the classic chemotactic CCL2/CCR2 axis of monocyte‒macrophages, leading to reduced recruitment of monocytes‒macrophages to the lungs, which decreased lung inflammation and prevented fibrotic progression. Both in vitro and in vivo findings demonstrated that MSC-MVs suppressed ERK1/2 phosphorylation followed by decreased CCL2 production to modulate monocyte-macrophage migration.
Our findings demonstrate that the protective effect of MSC-MVs against BLM-induced lung toxicity was achieved through the inhibition of the ERK1/2 signaling pathway, leading to the suppression of CCL2 expression and subsequent modulation of monocyte-macrophage migration, thereby establishing a theoretical basis for the effect of MSC-MVs in PF.
肺纤维化（PF）是一种发病率和死亡率都很高的疾病，但有效的治疗选择极其有限。间充质干细胞（MSCs）及其衍生物有望成为PF的潜在治疗方法。然而，这些有益作用的潜在机制仍知之甚少。本研究的目的是阐明人脐带间充质干细胞来源的微泡（MSC-MVs）减轻PF的具体机制。
通过组织学染色、流式细胞术和酶联免疫吸附测定（ELISA）评估MSC-MVs对博来霉素（BLM）诱导的小鼠PF的影响。通过RNA测序（RNA-seq）分析确定潜在的治疗靶点，随后通过实时定量聚合酶链反应（RT-qPCR）、ELISA、划痕试验和蛋白质印迹法（WB）进行验证。
MSC-MVs显著减轻了BLM诱导的小鼠肺部胶原纤维沉积，并下调了细胞外基质成分的表达。此外，这种治疗通过降低单核细胞-巨噬细胞比例以及TNF-α和IL-6水平，显著改善了肺部炎症。进一步分析表明，MSC-MVs抑制了单核细胞-巨噬细胞的经典趋化CCL2/CCR2轴，导致单核细胞-巨噬细胞向肺部的募集减少，从而减轻了肺部炎症并阻止了纤维化进展。体外和体内研究结果均表明，MSC-MVs抑制ERK1/2磷酸化，随后减少CCL2生成，以调节单核细胞-巨噬细胞迁移。
我们的研究结果表明，MSC-MVs对BLM诱导的肺毒性的保护作用是通过抑制ERK1/2信号通路实现的，导致CCL2表达受到抑制，随后调节单核细胞-巨噬细胞迁移，从而为MSC-MVs在PF中的作用建立了理论基础。
