Chung-Davidson Yu-Wen, Ren Jianfeng, Yeh Chu-Yin, Bussy Ugo, Huerta Belinda, Davidson Peter Joseph, Whyard Steven, Li Weiming
Department of Fisheries and Wildlife Michigan State University East Lansing MI.
Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources College of Fisheries and Life Sciences Shanghai Ocean University Shanghai China.
Hepatol Commun. 2019 Dec 24;4(2):219-234. doi: 10.1002/hep4.1461. eCollection 2020 Feb.
Biliary atresia (BA) is a rare neonatal disease with unknown causes. Approximately 10% of BA cases develop in utero with other congenital defects that span a large spectrum of disease variations, including degeneration of the gall bladder and bile duct as well as malformation of the liver, intestines, and kidneys. Similar developmental alterations are manifested in a unique animal model, the sea lamprey (), in which BA occurs naturally during metamorphosis. With the likelihood of conserved developmental mechanisms underlying organogenesis and degeneration, lamprey developmental BA may be a useful model to infer mechanisms underlying human embryonic BA. We reasoned that hepatobiliary transcriptomes regulate the transition between landmark stages of BA. Therefore, we examined sea lamprey hepatobiliary transcriptomes at four stages (M0, metamorphic stage 0 or larval stage, no BA; M2, metamorphic stage 2, onset of BA; M5, metamorphic stage 5, BA, and heightened hepatocyte proliferation and reorganization; and JV, juvenile, completion of BA) using messenger RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analyses. We found gene-expression patterns associated with the transition between these stages. In particular, transforming growth factor β (TGF-β), hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt, Wnt, and mitogen-activated protein kinase pathways were involved during biliary degeneration. Furthermore, disrupting the TGF-β signaling pathway with antagonist or small interfering RNA treatments at the onset of BA delayed gall bladder and bile duct degeneration. Distinctive gene-expression patterns are associated with the degeneration of the biliary system during developmental BA. In addition, disrupting TGF-β signaling pathway at the onset of BA delayed biliary degeneration.
胆道闭锁（BA）是一种病因不明的罕见新生儿疾病。约10%的BA病例在子宫内发病，伴有其他先天性缺陷，这些缺陷涵盖了广泛的疾病变异，包括胆囊和胆管退化以及肝脏、肠道和肾脏畸形。类似的发育改变在一种独特的动物模型——海七鳃鳗中也有体现，在其变态过程中会自然发生BA。鉴于器官发生和退化背后的发育机制可能具有保守性，七鳃鳗发育性BA可能是推断人类胚胎BA潜在机制的有用模型。我们推测肝胆转录组调控着BA标志性阶段之间的转变。因此，我们利用信使核糖核酸测序和京都基因与基因组百科全书通路分析，在四个阶段（M0，变态阶段0或幼虫阶段，无BA；M2，变态阶段2，BA开始；M5，变态阶段5，BA，肝细胞增殖和重组加剧；以及JV，幼体，BA完成）检测了海七鳃鳗的肝胆转录组。我们发现了与这些阶段之间转变相关的基因表达模式。特别是，转化生长因子β（TGF-β）、刺猬信号通路、磷脂酰肌醇-4,5-二磷酸3-激酶-Akt、Wnt和丝裂原活化蛋白激酶通路在胆管退化过程中发挥作用。此外，在BA开始时用拮抗剂或小干扰RNA处理破坏TGF-β信号通路，会延迟胆囊和胆管退化。发育性BA期间，独特的基因表达模式与胆道系统退化相关。此外，在BA开始时破坏TGF-β信号通路会延迟胆道退化。
