Yagai Tomoki, Miyajima Atsushi, Tanaka Minoru
Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Laboratory of Stem Cell Regulation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Am J Pathol. 2014 Aug;184(8):2250-9. doi: 10.1016/j.ajpath.2014.04.018. Epub 2014 Jun 12.
The liver has a remarkable capacity to regenerate after injury. Although the regulatory mechanisms of hepatocytic regeneration have been a subject of intense study, the dynamism of the sinusoids, specialized blood vessels in the liver, remains largely unknown. Transient activation of hepatic stellate cells and hepatic sinusoidal endothelial cells, which constitute the sinusoids, contributes to liver regeneration during acute injury, whereas their sustained activation causes liver fibrosis during chronic injury. We focused on understanding the association between damaged hepatocytes and sinusoidal regeneration or liver fibrogenesis using a carbon tetrachloride-induced liver injury mouse model. Damaged hepatocytes rapidly expressed semaphorin 3E (Sema3e), which induced contraction of sinusoidal endothelial cells and thereby contributed to activating hepatic stellate cells for wound healing. In addition, ectopic and consecutive expression of Sema3e in hepatocytes by the hydrodynamic tail-vein injection method resulted in disorganized regeneration of sinusoids and sustained activation of hepatic stellate cells. In contrast, liver fibrosis ameliorated in Sema3e-knockout mice compared with wild-type mice in a chronic liver injury model. Our results indicate that Sema3e, secreted by damaged hepatocytes, affects sinusoidal regeneration in a paracrine manner during liver regeneration, suggesting that Sema3e is a novel therapeutic target in liver fibrogenesis.
肝脏在损伤后具有显著的再生能力。尽管肝细胞再生的调控机制一直是深入研究的课题，但肝脏中特殊血管——肝血窦的动态变化在很大程度上仍不清楚。构成肝血窦的肝星状细胞和肝血窦内皮细胞的短暂激活有助于急性损伤期间的肝脏再生，而它们的持续激活则会在慢性损伤期间导致肝纤维化。我们利用四氯化碳诱导的肝损伤小鼠模型，重点研究受损肝细胞与肝血窦再生或肝纤维化形成之间的关联。受损肝细胞迅速表达信号素3E（Sema3e），其诱导肝血窦内皮细胞收缩，从而有助于激活肝星状细胞以促进伤口愈合。此外，通过流体动力学尾静脉注射法使Sema3e在肝细胞中异位且持续表达，导致肝血窦再生紊乱以及肝星状细胞持续激活。相比之下，在慢性肝损伤模型中，与野生型小鼠相比，Sema3e基因敲除小鼠的肝纤维化得到改善。我们的结果表明，受损肝细胞分泌的Sema3e在肝脏再生过程中以旁分泌方式影响肝血窦再生，提示Sema3e是肝纤维化形成中的一个新的治疗靶点。
