State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
Molecules. 2021 Apr 13;26(8):2231. doi: 10.3390/molecules26082231.
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.
枯否细胞（KCs）在肝再生中的作用复杂且存在争议。为了研究 F4/80 KC 在再生过程的不同阶段的独特作用，我们对小鼠进行了三分之二肝部分切除术（PHx）以诱导生理性肝再生。在 PHx 前或 PHx 后，通过腹腔内注射抗 F4/80 抗体（α-F4/80）清除 KC，以研究 F4/80 KC 在再生过程中的独特作用。在分离的 F4/80 KC 的 RNA 测序中，将起始阶段与进展阶段进行了比较。进行了 Ki67、HNF-4α、CD-31 和 F4/80 的免疫组织化学和免疫荧光染色以及 TGF-β2 通路的 Western blot。PHx 前 F4/80 KC 的耗竭将肝细胞增殖的峰值从 48 h 延迟至 120 h，而 PHx 后 F4/80 KC 的耗竭却导致肝细胞增殖持续抑制，表明 F4/80 KC 在肝再生的起始和进展阶段具有独特的作用。PHx 后 F4/80 KC 的耗竭可显著增加 TGF-β2 的血清水平，而 TGF-βRI 部分挽救了受损的肝细胞增殖。此外，PHx 后 F4/80 KC 的耗竭显著降低了白细胞介素 6 的关键下游介质之一——肿瘤坏死因子样细胞凋亡弱诱导因子（OSM）的表达，这对于肝再生期间的肝细胞增殖是必需的。在体内，重组 OSM（r-OSM）治疗缓解了 α-F4/80 对再生进展的抑制作用。总之，F4/80 KC 释放 OSM 以抑制 TGF-β2 的激活，通过释放增殖刹车来维持肝细胞增殖。
