Autophagy inhibition restores CD200 expression under IL-1β microenvironment in placental mesenchymal stem cells of fetal origin and improves its pulmonary fibrosis therapeutic potential.
Autophagy inhibition restores CD200 expression under IL-1β microenvironment in placental mesenchymal stem cells of fetal origin and improves its pulmonary fibrosis therapeutic potential.
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DOI：
10.1016/j.molimm.2022.08.014
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发表时间：
2022-09
影响因子：
3.6
通讯作者：
Wei Zhou;Li Li-Li;Jin Tao;Cunxiang Ma;Yawei Xie;Lu Ding;Shaozhang Hou;Zaiqi Zhang;D. Xue
中科院分区：
文献类型：
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作者：
Wei Zhou;Li Li-Li;Jin Tao;Cunxiang Ma;Yawei Xie;Lu Ding;Shaozhang Hou;Zaiqi Zhang;D. Xue
背景间充质干细胞（mesenchymal stem cells，MSCs）是治疗包括肺纤维化（pulmonary fibrosis，PF）在内的多种炎症性疾病的有效药物.然而，骨髓间充质干细胞在PF病理微环境中的特性仍不清楚。本研究通过观察胎儿胎盘间充质干细胞（fPMSCs）在IL-1β治疗和博莱霉素（BLM）诱导的肺纤维化小鼠模型中的自噬作用，探讨fPMSCs的自噬机制。在体外实验中，用IL-1β刺激fPMSC，以模拟肺纤维化的炎症微环境。通过检测巨噬细胞THP-1的活化情况、CD 200的表达情况、自噬标志物和MAPK信号通路，评价IL-1β对fPMSCs免疫抑制作用和自噬功能的影响。结果fPMSC属于CD 73 + CD 90 + CD 105 +/CD 14-CD 34-CD 45-HLA-DR-细胞，能够分化为成脂细胞、成骨细胞和成软骨细胞。此外，IL-1β可抑制fPMSCs对巨噬细胞的免疫抑制作用，并呈CD 200依赖性。sh-Atg 5慢病毒抑制自噬可增加CD 200的表达和CD 200阳性fPMSC的比例，并增强fPMSC对THP-1活化的免疫抑制。在机制上，IL-1β诱导的自噬受p38信号级联调节。在体内，Atg 5基因敲低诱导的fPMSCs自噬抑制导致PF小鼠模型抗纤维化作用增强。ConclusionsCollectively，来自炎症微环境的自噬抑制了MSCs的免疫抑制特性。基于此，调节自噬可能是促进其免疫调节和抗纤维化功效的有效途径。
BackgroundMesenchymal stem cells (MSCs) are promising remedies for various inflammatory disease including pulmonary fibrosis (PF). However, the properties of MSCs in PF pathological microenvironment remain unclear. In this study, the efficacy of autophagy in placental mesenchymal stem cells of fetal origin (fPMSCs) in either IL-1β treatment or BLM induced pulmonary fibrosis mice model was examined.MethodsThe characteristic of fPMSCs was identified by morphological observation, flow cytometry and differentiation potential. In vitro experiments, fPMSCs were stimulated with IL-1β, to mimic inflammatory microenvironment of pulmonary fibrosis. The immunosuppressive properties and autophagic function in fPMSCs treated with IL-1β were evaluated by both macrophage cells THP-1 activation and the expression of CD200 situation, autophagy marker and MAPK signaling pathway. The in vivo anti-fibrotic activity of fPMSCs interfering autophagy was evaluated by using BLM induced pulmonary fibrosis mice model.ResultsfPMSCs belonged to CD73+CD90+CD105+/CD14-CD34-CD45-HLA-DR-cells, and capable differentiation to adipogenic, osteogenic and chondrogenic cells. In addition, immunoinhibitory activity of fPMSCs for macrophage was restrained by IL-1β treatment in CD200 dependent manner. Suppression of autophagy by sh-Atg5 lentivirus increased the expression of CD200 and ratio of CD200 positive fPMSCs, and enhanced fPMSCs immunosuppression for THP-1 activation. Mechanistically, IL-1β induced autophagy regulated by p38 signaling cascade. In vivo, autophagy inhibition induced by Atg5 knockdown in fPMSCs resulted in strengthening antifibrotic effects on PF mice model.ConclusionsCollectively, autophagy derived from inflammatory microenvironment hampered the immunoinhibitory properties of MSCs. Based on this, adjustment of autophagy may be a valid approach to facilitate their immunomodulatory and anti-fibrotic efficacy.