AIF1 + CSF1R + MSCs, induced by TNF-α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis.
AIF1 + CSF1R + MSCs, induced by TNF-α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis.
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AIF1 CSF1R MSCs，由 TNFα 诱导，产生炎症微环境并促进肝癌发生
DOI：
10.1002/hep.32738
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发表时间：
2023-08-01
期刊：
影响因子：
13.5
通讯作者：
Wei, Lixin
中科院分区：
文献类型：
--
作者：
Zong, Chen;Meng, Yan;Ye, Fei;Yang, Xue;Li, Rong;Jiang, Jinghua;Zhao, Qiudong;Gao, Lu;Han, Zhipeng;Wei, Lixin
越来越多的证据表明，间充质干细胞(MSCs)是肝脏受损局部组织和肿瘤微环境的家园。慢性炎症被认为是原发性肝癌的主要特征。然而，内源性MSCs在炎症环境中的特征及其在肝癌发生中的作用尚不清楚。利用单细胞RNA测序，我们鉴定了一个明显的炎症相关的MSCs亚群，即AIF1+CSF1R+MSCs，它存在于肝癌发生前的微环境中。此外，我们还发现该MSC亚群可能是由肿瘤坏死因子-α通过肿瘤坏死因子受体1/sirtuin1(Sirtuin1)途径诱导的。在大鼠原发性肝癌模型中，我们发现高表达SIRT1的MSCs(Ad-Sirt1-MSCs)通过分泌C-C基序趋化因子配体(CCL)5促进巨噬细胞募集并协同促进肝癌的发生。有趣的是，巨噬细胞的耗尽或CCL5表达的下调减弱了Ad-Sirt1-MSCs对肝脏炎症和肝癌发生(HCG)的促进作用。最后，我们证明SIRT1通过激活AKT/HIF1α信号轴上调MSC中CCL5的表达。综上所述，我们的结果表明，动员到损伤部位的MSCs可以被巨噬细胞教育。反过来，受过教育的MSCs参与产生慢性炎症微环境并促进HCG。
Increasing evidence suggests that mesenchymal stem cells (MSCs) home to injured local tissues and the tumor microenvironment in the liver. Chronic inflammation is regarded as the major trait of primary liver cancer. However, the characteristics of endogenous MSCs in the inflammatory environment and their role in the occurrence of liver cancer remain obscure. Using single‐cell RNA sequencing, we identified a distinct inflammation‐associated subset of MSCs, namely AIF1+CSF1R+ MSCs, which existed in the microenvironment before the occurrence of liver cancer. Furthermore, we found that this MSC subgroup is likely to be induced by TNF‐α stimulation through the TNFR1/SIRT1 (sirtuin 1) pathway. In a rat primary liver cancer model, we showed that MSCs with high SIRT1 expression (Ad‐Sirt1‐MSCs) promoted macrophage recruitment and synergistically facilitated liver cancer occurrence by secreting C‐C motif chemokine ligand (CCL) 5. Interestingly, depletion of macrophages or knockdown of CCL5 expression in Ad‐Sirt1‐MSCs attenuated the promotive effect of Ad‐Sirt1‐MSCs on liver inflammation and hepatocarcinogenesis (HCG). Finally, we demonstrated that SIRT1 up‐regulated CCL5 expression through activation of the AKT/HIF1α signaling axis in MSCs. Together, our results show that MSCs, which are mobilized to the injured site, can be educated by macrophages. In turn, the educated MSCs are involved in generating a chronic inflammatory microenvironment and promoting HCG.
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影响因子：
64.5
作者：
Baryawno, Ninib;Przybylski, Dariusz;Scadden, David T.
通讯作者：
Scadden, David T.
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影响因子：
5.3
作者：
Bai X;Xi J;Bi Y;Zhao X;Bing W;Meng X;Liu Y;Zhu Z;Song G
通讯作者：
Song G
影响因子：
9.7
作者：
Nakao Y;Fukuda T;Zhang Q;Sanui T;Shinjo T;Kou X;Chen C;Liu D;Watanabe Y;Hayashi C;Yamato H;Yotsumoto K;Tanaka U;Taketomi T;Uchiumi T;Le AD;Shi S;Nishimura F
通讯作者：
Nishimura F
影响因子：
23.9
作者：
Leimkühler NB;Gleitz HFE;Ronghui L;Snoeren IAM;Fuchs SNR;Nagai JS;Banjanin B;Lam KH;Vogl T;Kuppe C;Stalmann USA;Büsche G;Kreipe H;Gütgemann I;Krebs P;Banz Y;Boor P;Tai EW;Brümmendorf TH;Koschmieder S;Crysandt M;Bindels E;Kramann R;Costa IG;Schneider RK
通讯作者：
Schneider RK
影响因子：
13.5
作者：
Liu, Jie;Godlewski, Grzegorz;Kunos, George
通讯作者：
Kunos, George