过表达HGF的人牙髓基质细胞（HGF-DPSCs）通过调控小鼠肺黏膜CCR1+ Th2细胞反应缓解哮喘
2025/04/06
摘要
背景：哮喘是一种全球约3亿患者受累的常见过敏性疾病，仍是重大公共卫生挑战。间充质基质细胞（MSCs）与肝细胞生长因子（HGF）均具有免疫调节特性，在哮喘治疗中展现出潜力，但其具体作用机制尚未完全阐明。
目的：本研究旨在构建过表达人源HGF的人牙髓基质细胞（HGF-DPSCs），评估其对哮喘的治疗效果并解析其作用机制。
结果：实验表明，构建的HGF-DPSCs在体外及体内均稳定过表达HGF，且相较于普通DPSCs，其在肺组织中的分布更为显著。在屋尘螨（HDM）诱导的哮喘模型中，HGF-DPSCs较DPSCs表现出更强的气道高反应性（AHR）抑制能力，并显著减轻炎症浸润及CD4+ T细胞肺内募集。免疫荧光分析显示，HGF-DPSCs与肺上皮细胞存在空间共定位。蛋白质芯片分析鉴定出趋化因子Ckβ8-1为HGF-DPSCs与支气管上皮细胞（Beas-2B）相互作用的关键介质。进一步机制研究表明，HGF-DPSCs干预可显著降低哮喘小鼠肺内Ckβ8-1蛋白表达及CD4+CCR1+ T淋巴细胞比例。通过Ckβ8-1拮抗剂联合Transwell迁移实验证实，该趋化因子对CD4+ T细胞迁移具有显著促进作用。流式细胞术分析显示，哮喘小鼠肺内CD4+CCR1+ T细胞呈现典型Th2表型特征，表现为IL-4、IL-5及IL-13等细胞因子的高表达。
结论：HGF-DPSCs通过调控Ckβ8-1/CCR1轴抑制CCR1+ Th2细胞反应，从而缓解HDM诱导的哮喘病理进程，为哮喘治疗提供了基于细胞工程的新型策略。
背景：哮喘是一种全球约3亿患者受累的常见过敏性疾病，仍是重大公共卫生挑战。间充质基质细胞（MSCs）与肝细胞生长因子（HGF）均具有免疫调节特性，在哮喘治疗中展现出潜力，但其具体作用机制尚未完全阐明。
目的：本研究旨在构建过表达人源HGF的人牙髓基质细胞（HGF-DPSCs），评估其对哮喘的治疗效果并解析其作用机制。
结果：实验表明，构建的HGF-DPSCs在体外及体内均稳定过表达HGF，且相较于普通DPSCs，其在肺组织中的分布更为显著。在屋尘螨（HDM）诱导的哮喘模型中，HGF-DPSCs较DPSCs表现出更强的气道高反应性（AHR）抑制能力，并显著减轻炎症浸润及CD4+ T细胞肺内募集。免疫荧光分析显示，HGF-DPSCs与肺上皮细胞存在空间共定位。蛋白质芯片分析鉴定出趋化因子Ckβ8-1为HGF-DPSCs与支气管上皮细胞（Beas-2B）相互作用的关键介质。进一步机制研究表明，HGF-DPSCs干预可显著降低哮喘小鼠肺内Ckβ8-1蛋白表达及CD4+CCR1+ T淋巴细胞比例。通过Ckβ8-1拮抗剂联合Transwell迁移实验证实，该趋化因子对CD4+ T细胞迁移具有显著促进作用。流式细胞术分析显示，哮喘小鼠肺内CD4+CCR1+ T细胞呈现典型Th2表型特征，表现为IL-4、IL-5及IL-13等细胞因子的高表达。
结论：HGF-DPSCs通过调控Ckβ8-1/CCR1轴抑制CCR1+ Th2细胞反应，从而缓解HDM诱导的哮喘病理进程，为哮喘治疗提供了基于细胞工程的新型策略。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Cytotherapy. 2025 Feb 24:S1465-3249(25)00063-5DOI: 10.1016/j.jcyt.2025.02.005.）
HGF-DPSCs ameliorate asthma by regulating CCR1+ Th2 cells responses in mice pulmonary mucosa
Geng Lin, Mengyu Tao, Heqiang Sun, Xinli Deng, Letong Zhang, Guixiang Sun, Yong Zhou, Guogang Xu.
Abstract
BACKGROUND: Asthma, a prevalent allergic disease affecting approximately 300 million individuals globally, remains a significant public health challenge. Mesenchymal stromal cells (MSCs) and hepatocyte growth factor (HGF), both recognized for their immunomodulatory properties, hold therapeutic potential for asthma. However, their precise mechanisms remain underexplored.
OBJECTIVE: The current study aimed to engineer human HGF overexpressing human dental pulp stromal cells (HGF-DPSCs) and evaluate their efficacy in asthma management while elucidating underlying mechanisms.
RESULTS:The results showed that the constructed HGF-DPSCs overexpressed HGF both in vitro and in vivo. Also, compared with DPSCs, they demonstrated a more pronounced distribution within lung tissue. In house dust mite (HDM)-induced asthma, HGF-DPSCs showed a more significant inhibitory effect on airway hyperresponsiveness (AHR), inflammatory infiltration, and CD4+ T-cell recruitment compared with DPSCs. Immunofluorescence analysis revealed a spatial overlap between HGF-DPSCs and pulmonary epithelial cells. Protein array analysis identified the chemokine Ckβ8-1 as a pivotal factor in the interaction between HGF-DPSCs and bronchial epithelial Beas-2B cells. Subsequent mechanistic investigations demonstrated that administration of HGF-DPSCs markedly reduced both the expression of Ckβ8-1 protein and the proportion of CD4+CCR1+ T lymphocytes in the lungs of asthmatic mice. Furthermore, transwell migration assays incorporating a CKβ8-1 antagonist revealed a significant inhibition of CD4+ T-cell migration. Flow cytometry analysis indicated that CD4+CCR1+ T cells from the lungs of asthmatic mice exhibit a pronounced Th2 phenotype, characterized by high expression levels of IL-4, IL-5, and IL-13 cytokines.
CONCLUSION: In conclusion, HGF-DPSCs ameliorate HDM-induced asthma by suppressing CCR1+ Th2 cell responses via modulation of the Ckβ8-1/CCR1 axis, highlighting their potential as a novel therapeutic strategy.
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哮喘中基底膜区增厚的临床与生物学特征
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补充牛磺酸可减轻因次氯酸暴露而加重的哮喘气道炎症
