F4/80(+) Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway.
F4/80(+) Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway.
复制标题
F4/80（+）Kupffer细胞衍生的Oncostatin M通过抑制TGF-β2途径来维持肝脏再生的进展阶段。
DOI：
10.3390/molecules26082231
复制
发表时间：
2021-04-13
期刊：
影响因子：
--
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Lu Q;Shen H;Yu H;Fu J;Dong H;Chen Y;Wang H
库普弗细胞（KCs）在肝脏再生中的作用是复杂而有争议的。为了研究F4/80+ KCs在再生过程中不同阶段的不同作用，我们在小鼠身上进行了三分之二的部分肝切除术（PHx）以诱导生理性肝再生。在phx前后，通过腹腔注射抗F4/80抗体（α-F4/80）来清除KCs，以研究F4/80+ KCs在再生过程中的独特作用。在分离的F4/80+ KCs的RNA测序中，比较了起始期和进展期。对Ki67、HNF-4α、CD-31、F4/80进行免疫组化、免疫荧光染色，对TGF-β2通路进行Western blot检测。在phx前，F4/80+ KCs的缺失将肝细胞增殖的峰值从48小时延迟到120小时，而在phx后，F4/80+ KCs的缺失意外地导致肝细胞增殖的持续抑制，这表明F4/80+ KCs在肝再生的起始和进展阶段具有独特的作用。phx后F4/80+ KC缺失可显著提高血清TGF-β2水平，而TGF-βRI可部分恢复受损的肝细胞增殖。此外，在phx后，F4/80+ KC的缺失显著降低了抑癌素M （OSM）的表达，OSM是白细胞介素-6的关键下游介质，在肝脏再生过程中是肝细胞增殖所必需的。在体内，重组OSM （r-OSM）处理减轻了α-F4/80对再生进展的抑制作用。总的来说，F4/80+ KCs释放OSM抑制TGF-β2的激活，通过释放增殖制动器维持肝细胞增殖。
The role of Kupffer cells (KCs) in liver regeneration is complicated and controversial. To investigate the distinct role of F4/80+ KCs at the different stages of the regeneration process, two-thirds partial hepatectomy (PHx) was performed in mice to induce physiological liver regeneration. In pre- or post-PHx, the clearance of KCs by intraperitoneal injection of the anti-F4/80 antibody (α-F4/80) was performed to study the distinct role of F4/80+ KCs during the regenerative process. In RNA sequencing of isolated F4/80+ KCs, the initiation phase was compared with the progression phase. Immunohistochemistry and immunofluorescence staining of Ki67, HNF-4α, CD-31, and F4/80 and Western blot of the TGF-β2 pathway were performed. Depletion of F4/80+ KCs in pre-PHx delayed the peak of hepatocyte proliferation from 48 h to 120 h, whereas depletion in post-PHx unexpectedly led to persistent inhibition of hepatocyte proliferation, indicating the distinct role of F4/80+ KCs in the initiation and progression phases of liver regeneration. F4/80+ KC depletion in post-PHx could significantly increase TGF-β2 serum levels, while TGF-βRI partially rescued the impaired proliferation of hepatocytes. Additionally, F4/80+ KC depletion in post-PHx significantly lowered the expression of oncostatin M (OSM), a key downstream mediator of interleukin-6, which is required for hepatocyte proliferation during liver regeneration. In vivo, recombinant OSM (r-OSM) treatment alleviated the inhibitory effect of α-F4/80 on the regenerative progression. Collectively, F4/80+ KCs release OSM to inhibit TGF-β2 activation, sustaining hepatocyte proliferation by releasing a proliferative brake.
登录
查看更多内容
影响因子：
15.9
作者：
Bedoret, Denis;Wallemacq, Hugues;Bureau, Fabrice
通讯作者：
Bureau, Fabrice
影响因子：
2.3
作者：
An, Shucai;Soe, Kyaw;Koji, Takehiko
通讯作者：
Koji, Takehiko
影响因子：
25.7
作者：
Boulton, RA;Alison, MR;Hodgson, HJF
通讯作者：
Hodgson, HJF
影响因子：
2.4
作者：
Haldrup, David;Heeboll, Sara;Gronbaek, Henning
通讯作者：
Gronbaek, Henning
影响因子：
6
作者：
Kang LI;Mars WM;Michalopoulos GK
通讯作者：
Michalopoulos GK