PDF(Pubmed)
Abstract：
Liver regeneration is a complex process involving the crosstalk between parenchymal and non-parenchymal cells, especially macrophages. However, the underlying mechanisms remain incompletely understood. Here, we identify the E3 ubiquitin ligase TRIM26 as a crucial regulator of liver regeneration. Following partial hepatectomy or acute liver injury induced by carbon tetrachloride, Trim26 knockout mice exhibit enhanced hepatocyte proliferation compared to wild-type controls, while adeno-associated virus (AAV)-mediated overexpression of Trim26 reverses the promotional effects. Mechanistically, Trim26 deficiency promotes the recruitment of macrophages to the liver and their polarization towards pro-inflammatory M1 phenotype. These M1 macrophages secrete Wnts, including Wnt2, which subsequently stimulate hepatocyte proliferation through the activation of Wnt/β-catenin signaling. In hepatocytes, Trim26 knockdown reduces the ubiquitination and degradation of β-catenin, thereby further enhancing Wnt/β-catenin signaling. Pharmacological inhibition of Wnt/β-catenin pathway by ICG-001 or depletion of macrophages by clodronate liposomes diminishes the pro-regenerative effects of Trim26 deficiency. Moreover, bone marrow transplantation experiments provide evidence that Trim26 knockout in myeloid cells alone can also promote liver regeneration, highlighting the critical role of macrophage Trim26 in this process. Taken together, our study uncovers TRIM26 as a negative regulator of liver regeneration by modulating macrophage polarization and Wnt/β-catenin signaling in hepatocytes, providing a potential therapeutic target for promoting liver regeneration in clinical settings.
摘要：
肝再生是一个复杂的过程，涉及实质细胞和非实质细胞之间的串扰，尤其是巨噬细胞.然而,潜在的机制仍未完全理解。这里,我们确定E3泛素连接酶TRIM26是肝脏再生的关键调节因子。在部分肝切除术或四氯化碳引起的急性肝损伤后，与野生型对照相比，Trim26敲除小鼠表现出增强的肝细胞增殖，而腺相关病毒（AAV）介导的Trim26过表达逆转了促进作用。机械上,Trim26缺乏促进巨噬细胞向肝脏的募集及其向促炎M1表型的极化。这些M1巨噬细胞分泌Wnts，包括Wnt2,其随后通过激活Wnt/β-连环蛋白信号刺激肝细胞增殖。在肝细胞中，Trim26敲除减少β-catenin的泛素化和降解，从而进一步增强Wnt/β-连环蛋白信号传导。ICG-001对Wnt/β-连环蛋白途径的药理学抑制或氯膦酸盐脂质体对巨噬细胞的消耗减弱了Trim26缺乏症的促再生作用。此外，骨髓移植实验提供的证据表明，Trim26基因敲除单独在髓系细胞中也可以促进肝再生，强调巨噬细胞Trim26在这一过程中的关键作用。一起来看,我们的研究揭示了TRIM26作为肝再生的负调节因子通过调节巨噬细胞极化和Wnt/β-catenin信号在肝细胞中，为促进临床肝脏再生提供了一个潜在的治疗靶点。
