Mesenchymal stem cells induce dendritic cell immune tolerance via paracrine hepatocyte growth factor to alleviate acute lung injury
Mesenchymal stem cells induce dendritic cell immune tolerance via paracrine hepatocyte growth factor to alleviate acute lung injury
复制标题
间充质干细胞通过旁分泌肝细胞生长因子诱导树突状细胞免疫耐受减轻急性肺损伤
DOI：
10.1186/s13287-019-1488-2
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发表时间：
2019-12-04
影响因子：
7.5
通讯作者：
Liu, Ling
中科院分区：
文献类型：
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作者：
Lu, Zhonghua;Chang, Wei;Liu, Ling
间充质干细胞(MSCs)可通过旁分泌肝细胞生长因子(HGF)减轻急性肺损伤(ALI)，诱导树突状细胞(DC)分化为耐受树突状细胞(DCregs)，并参与免疫反应。然而，MSCs是否通过分泌HGF来缓解早期ALI而诱导DCregs的产生仍不清楚。小鼠骨髓间充质干细胞对脂多糖诱导的ALI的保护作用是通过诱导成熟DC分化为DCregs来实现的，其机制与肝细胞生长因子/AKT信号通路的激活有关。方法用Transwell系统将小鼠骨髓间充质干细胞或肝细胞生长因子高表达或表达下调的骨髓间充质干细胞与小鼠骨髓来源的树突状细胞共培养3天。用MSC或HGF高表达或下调的MSCs治疗脂多糖诱导的ALI小鼠24 h，用流式细胞仪检测DC的吞噬、聚集、成熟以及T细胞的增殖情况。通过肺湿重/体重比(LWW/BW)和组织病理学分析评价肺损伤程度。此外，我们在共培养体系中使用Akt抑制剂MK-2206来阐明肝细胞生长因子/Akt信号通路在调节早期ALI小鼠DC分化为调节性DC和减轻肺损伤中的作用。结果未成熟DC(ImDC)在脂多糖(50 ng/ml)刺激24 h后可诱导成熟。MSCs或HGF诱导MDCs分化为调节性DC，其特点是低表达MHCII、CD86和CD40分子，吞噬功能强，并具有抑制T细胞增殖的能力。MSCs对DCregs的作用随HGF分泌增加而增强，随HGF分泌减少而减弱。重组HGF诱导的DCregs可被Akt抑制剂MK-2206减弱。内毒素诱导的ALI小鼠肺DC聚集率和MDC比率增加，而MSCs治疗可降低肺DC聚集率和成熟度，减轻肺病理损伤。HGF基因的高表达增强了MSCs的上述作用，而HGF基因的低表达减弱了MSCs的上述作用。结论MSCs通过旁分泌HGF诱导MDCs向调节性DC分化，从而减轻早期ALI。此外，HGF诱导MDCs分化为DCregs的机制与Akt通路的激活有关。
BackgroundMesenchymal stem cells (MSCs) have been shown to alleviate acute lung injury (ALI) via paracrine hepatocyte growth factor (HGF) and to induce the differentiation of dendritic cells (DCs) into tolerogenic dendritic cells (DCregs) and participate in the immune response. However, whether MSCs induce the production of DCregs by secreting HGF to alleviate early ALI remains unclear. We observed that the protective effect of mouse bone marrow-derived MSCs against lipopolysaccharide (LPS)-induced ALI was achieved by inducing mature DCs (mDCs) to differentiate into DCregs, and its mechanism is related to the activation of the HGF/Akt pathway.MethodsMSCs or MSCs with overexpression or knockdown of HGF were cocultured with DCs derived from mouse bone marrow using a Transwell system for 3 days. Moreover, we used MSCs or MSCs with overexpression or knockdown of HGF to treat LPS-induced ALI mice for 24 h. Flow cytometry was performed to measure the phagocytosis, accumulation, and maturation of DCs, as well as proliferation of T cells. Lung injury was estimated by lung wet weight to body weight ratio (LWW/BW) and histopathological analysis. Furthermore, we used the Akt inhibitor MK-2206 in a coculture system to elucidate the role of the HGF/Akt pathway in regulating the differentiation of DCs into regulatory DCs and relieving lung injury in early ALI mice.ResultsImmature DCs (imDCs) were induced to mature after 24 h of LPS (50 ng/ml) stimulation. MSCs or HGF induced the differentiation of mDCs into regulatory DCs characterized by low expression of MHCII, CD86, and CD40 molecules, strong phagocytic function, and the ability to inhibit T cell proliferation. The effect of MSCs on DCregs was enhanced with the increase in HGF secretion and was weakened with the decrease in HGF secretion. DCregs induced by recombinant HGF were attenuated by the Akt inhibitor MK-2206. Lung DC aggregation and mDC ratio increased in LPS-induced ALI mice, while treatment with MSCs decreased lung DC aggregation and maturation and alleviated lung pathological injury. High expression of the HGF gene enhanced the above effect of MSCs, while decreased expression of HGF weakened the above effect of MSCs.ConclusionsMSCs alleviate early ALI via paracrine HGF by inducing mDCs to differentiate into regulatory DCs. Furthermore, the mechanism of HGF-induced differentiation of mDCs into DCregs is related to the activation of the Akt pathway.