骨髓间充质干细胞来源的外泌体通过miR-30b/Wnt5a通路抑制慢性阻塞性肺疾病小鼠肺微血管内皮细胞凋亡
Bone Marrow Mesenchymal Stem Cells-Derived Exosomes Inhibit Apoptosis of Pulmonary Microvascular Endothelial Cells in COPD Mice Through miR-30b/Wnt5a Pathway.
作者信息
Song Qing, Zhou Aiyuan, Cheng Wei, Zhao Yiyang, Liu Cong, Zeng Yuqin, Lin Ling, Zhou Zijing, Peng Yating, Chen Ping
机构信息
Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China.
Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, 410011, People's Republic of China.
出版信息
Int J Nanomedicine. 2025 Jan 30;20:1191-1211. doi: 10.2147/IJN.S487097. eCollection 2025.
BACKGROUND
Bone marrow mesenchymal stem cells (BMSCs)-derived exosomes are rich in a variety of active substances, including microRNA (miR) and have shown powerful therapeutic effects to ameliorate cell injury and diseases. However, the role of BMSCs-derived exosomes on chronic obstructive pulmonary disease (COPD) has been poorly studied. In addition, pulmonary microvascular endothelial cells (PMVECs) apoptosis contributes to the onset of COPD. Inhibition of PMVECs apoptosis can reverse COPD changes. Therefore, the aim of this study was to explore the role of BMSCs-derived exosomes in the apoptosis of PMVECs in COPD and to investigate the potential mechanisms.
METHODS
We isolated and characterized normal mouse BMSCs-derived exosomes and PMVECs. We performed miR sequencing of BMSCs-derived exosomes. We transfected PMVECs with the miR-30b mimic and Wnt5a overexpression plasmid to assess the underlying mechanisms. Cigarette smoke extract (CSE)-induced COPD mice were treated with exosomes and HBLV-mmu-miR-30b via intratracheal instillation. Finally, we determined the expression of miR-30b and Wnt5a in tissues from patients with COPD.
RESULTS
BMSCs-derived exosomes could significantly reduce apoptosis of CSE-induced PMVECs and increase the expression of miR-30b (<0.05). Based on miR sequencing, miR-30b was highly enriched in BMSCs-derived exosomes. The knockdown of miR-30b in BMSCs-derived exosomes could increase the apoptosis of CSE-induced PMVECs (<0.05). miR-30b overexpression significantly reduced apoptosis and repressed Wnt5a protein expression in CSE-induced PMVECs (<0.05). Furthermore, Wnt5a overexpression reversed the anti-apoptotic effect of miR-30b on CSE-induced PMVECs (<0.05). In addition, compared with the COPD group, treatment with BMSCs-derived exosomes and miR-30b overexpression could alleviate emphysema changes, decrease the mean linear intercept and alveolar destructive index, reduce apoptosis, increase the expression of miR-30b, and decrease the expression of Wnt5a in lung tissue (<0.05). Finally, miR-30b expression was decreased in patients with COPD, while Wnt5a expression was increased in these patients (<0.05).
CONCLUSION
BMSCs-derived exosomes could improve the damage of COPD perhaps by delivering miR-30b. miR-30b could reduce apoptosis of CSE-induced PMVECs by targeting Wnt5a.
背景
骨髓间充质干细胞（BMSCs）来源的外泌体富含多种活性物质，包括微小RNA（miR），并已显示出强大的治疗作用，可改善细胞损伤和疾病。然而，BMSCs来源的外泌体对慢性阻塞性肺疾病（COPD）的作用研究较少。此外，肺微血管内皮细胞（PMVECs）凋亡促成了COPD的发病。抑制PMVECs凋亡可逆转COPD的变化。因此，本研究旨在探讨BMSCs来源的外泌体在COPD中PMVECs凋亡中的作用，并研究其潜在机制。
方法
我们分离并鉴定了正常小鼠BMSCs来源的外泌体和PMVECs。我们对BMSCs来源的外泌体进行了miR测序。我们用miR-30b模拟物和Wnt5a过表达质粒转染PMVECs以评估潜在机制。通过气管内滴注用外泌体和HBLV-mmu-miR-30b治疗香烟烟雾提取物（CSE）诱导的COPD小鼠。最后，我们测定了COPD患者组织中miR-30b和Wnt5a的表达。
结果
BMSCs来源的外泌体可显著减少CSE诱导的PMVECs凋亡，并增加miR-30b的表达（<0.05）。基于miR测序，miR-30b在BMSCs来源的外泌体中高度富集。敲低BMSCs来源外泌体中的miR-30b可增加CSE诱导的PMVECs凋亡（<0.05）。miR-30b过表达显著减少CSE诱导的PMVECs凋亡并抑制Wnt5a蛋白表达（<0.05）。此外，Wnt5a过表达逆转了miR-30b对CSE诱导的PMVECs的抗凋亡作用（<0.05）。此外，与COPD组相比，用BMSCs来源的外泌体和miR-30b过表达治疗可减轻肺气肿变化，降低平均线性截距和肺泡破坏指数，减少凋亡，增加肺组织中miR-30b的表达，并降低Wnt5a的表达（<0.05）。最后，COPD患者中miR-30b表达降低，而这些患者中Wnt5a表达增加（<0.05）。
结论
BMSCs来源的外泌体可能通过传递miR-30b改善COPD的损伤。miR-30b可通过靶向Wnt5a减少CSE诱导的PMVECs凋亡。
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