Institute for Stem Cell Biology and Regenerative Medicine, Department of Developmental Biology, Howard Hughes Medical Institute, Stanford School of Medicine, Stanford, CA.
Medical Scientist Training Program, Stanford School of Medicine, Stanford, CA.
Hepatology. 2019 Jun;69(6):2623-2635. doi: 10.1002/hep.30563. Epub 2019 Apr 9.
In the liver, Wnt/β-catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl ) toxicity. Following injury, peri-injury hepatocytes become Wnt-responsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri-injury Axin2 hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2 descendants. Using single-cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl toxicity. Induced loss of β-catenin in peri-injury hepatocytes results in delayed repair and ultimately injury-induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/β-catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wnt-producing regulator of liver tissue repair following localized liver injury.
在肝脏中，Wnt/β-连环蛋白信号通路参与调节稳态下的区域化和肝细胞增殖。我们研究了损伤后的 Wnt 基因表达和信号转导，通过原位杂交显示 Wnts 被急性四氯化碳（CCl）毒性激活。损伤后，损伤周围的肝细胞变得对 Wnt 有反应，表达 Wnt 靶基因轴抑制蛋白 2（Axin2）。损伤周围 Axin2 肝细胞的谱系追踪表明，在恢复过程中，损伤的实质由 Axin2 后代重新填充和修复。通过单细胞 RNA 测序，我们表明内皮细胞是急性 CCl 毒性后 Wnts 的主要来源。诱导损伤周围肝细胞中β-连环蛋白缺失会导致修复延迟，最终导致损伤诱导的致死性，而内皮细胞中 Wnt 产生的缺失会导致损伤后增殖反应的延迟。结论：我们的研究结果强调了 Wnt/β-连环蛋白信号通路在急性肝毒性后恢复组织完整性中的重要性，并确立了内皮细胞作为局部肝损伤后肝组织修复中重要的 Wnt 产生调节剂的作用。
