Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells.
Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells.
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间充质干细胞通过诱导调节性树突状细胞减轻细菌引起的小鼠肝损伤
DOI：
10.1002/hep.26670
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发表时间：
2014-02
期刊：
影响因子：
13.5
通讯作者：
Zhang, Yanyun
中科院分区：
文献类型：
--
作者：
Zhang, Yi;Cai, Wei;Huang, Qingrong;Gu, Yuting;Shi, Yufang;Huang, Jiefang;Zhao, Fang;Liu, Qiang;Wei, Xunbin;Jin, Min;Wu, Changping;Xie, Qing;Zhang, Yi;Wan, Bing;Zhang, Yanyun
暴发性肝衰竭（FHF）是一种以肝功能突然严重受损为特征的临床综合征。间充质干细胞（MSCs）已被提议作为治疗FHF的一种有前景的方法。在本研究中，我们使用痤疮丙酸杆菌（P. acnes）致敏、脂多糖（LPS）诱导的小鼠肝损伤作为人类FHF的动物模型。我们证明了MSCs的给药显著改善了肝损伤，并提高了痤疮丙酸杆菌加LPS诱导的FHF小鼠的存活率。同种异体MSCs在FHF中显示出与自体MSCs相似的治疗效果。MSCs的治疗效果可归因于肝脏中CD4 + T细胞浸润和活化的减少、辅助性T细胞1的抑制以及调节性T细胞（Tregs）的诱导。此外，在MSCs治疗的小鼠肝脏中检测到痤疮丙酸杆菌的DNA拷贝数减少。有趣的是，MSCs诱导产生了一种独特的肝脏CD11c + MHCIIhiCD80loCD86lo调节性树突状细胞（DCs）群体。而且，这些DCs通过产生转化生长因子 - β诱导Treg分化。进一步的机制研究表明，MSCs衍生的前列腺素E2及其受体之一EP4以磷脂酰肌醇3 - 激酶依赖的方式在CD11c + B220 - DC前体分化为调节性DCs中起关键作用。结论：MSCs诱导CD11c + B220 - DC前体分化为调节性DCs。本研究阐明了MSCs的一种免疫调节机制，并为MSCs在FHF治疗中的应用奠定了基础。（《肝脏病学》2014年；59卷：671 - 682页）
Fulminant hepatic failure (FHF) is a clinical syndrome characterized by sudden and severe impairment of liver function. Mesenchymal stem cells (MSCs) have been proposed as a promising therapeutic approach for FHF. In this study we used Propionibacterium acnes (P. acnes)‐primed, lipopolysaccharide (LPS)‐induced liver injury in mice as an animal model of human FHF. We demonstrated that administration of MSCs significantly ameliorated liver injury and improved the survival rates of mice subjected to P. acnes plus LPS‐induced FHF. Allogeneic MSCs showed similar treatment efficacy as autologous MSCs did in FHF. Treatment efficacy of MSCs could be attributed to decreased infiltration and activation of CD4+ T cells in the liver, inhibition of T helper 1 cells, and induction of regulatory T cells (Tregs). Moreover, decreased DNA copies of P. acnes were detected in the liver of MSC‐treated mice. Intriguingly, a distinct liver population of CD11c+MHCIIhiCD80loCD86lo regulatory dendritic cells (DCs) was induced by MSCs. Moreover, these DCs induced Treg differentiation through transforming growth factor‐β production. Further mechanistic studies demonstrated that MSC‐derived prostaglandin E2 and one of its receptors, EP4, played essential roles in the differentiation of CD11c+B220− DC precursors into regulatory DCs in a phosphoinositide 3‐kinase‐dependent manner. Conclusion: MSCs induce regulatory DCs from CD11c+B220− DC precursors. This study elucidates an immunoregulatory mechanism of MSCs and lays a foundation for application of MSCs in FHF therapy. (Hepatology 2014;59:671–682)
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