Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA.
Hepatol Int. 2021 Feb;15(1):166-178. doi: 10.1007/s12072-020-10119-w. Epub 2021 Jan 24.
GATA6, a transcription factor expressed in cholangiocytes, has been implicated in the response to liver injury. In biliary atresia, a disease characterized by extrahepatic bile duct obstruction, liver expression of GATA6 increases with pathological bile duct expansion and decreases after successful Kasai portoenterostomy. The aim of this study was to garner genetic evidence that GATA6 is involved in ductular formation/expansion.
The murine Gata6 gene was conditionally deleted using Alb-cre, a transgene expressed in hepatoblasts (the precursors of hepatocytes and cholangiocytes) and mature hepatocytes. Bile duct ligation (BDL) was used to model biliary obstruction.
Alb-Cre;Gata6 mice were viable and fertile. Cre-mediated recombination of Gata6 in hepatocytes had little impact on cellular structure or function. GATA6 immunoreactivity was retained in a majority of biliary epithelial cells in adult Alb-Cre;Gata6 mice, implying that surviving cholangiocytes were derived from hepatoblasts that had escaped biallelic Cre-mediated recombination. Although GATA6 immunoreactivity was preserved in cholangiocytes, Alb-cre;Gata6 mice had a demonstrable biliary phenotype. A neutrophil-rich infiltrate surrounded newly formed bile ducts in neonatal Alb-Cre;Gata6 mice. Foci of fibrosis/necrosis, presumed to reflect patchy defects in bile duct formation, were observed in the livers of 37% of adult Alb-cre;Gata6 mice and 0% of controls (p < 0.05). Most notably, Alb-cre;Gata6 mice had an altered response to BDL manifest as reduced survival, impaired bile ductule proliferation, increased parenchymal necrosis, reduced fibrosis, and enhanced macrophage accumulation in the portal space.
GATA6 orchestrates intrahepatic biliary remodeling and mitigates liver injury following extrahepatic bile duct obstruction.
GATA6 是一种在胆管细胞中表达的转录因子，已被牵连到肝损伤的反应中。在胆道闭锁中，一种以肝外胆管阻塞为特征的疾病，肝内 GATA6 的表达随着病理性胆管扩张而增加，并在成功的 Kasai 门腔分流术后减少。本研究的目的是获得遗传证据，证明 GATA6 参与了胆管形成/扩张。
使用 Alb-cre，一种在肝母细胞（肝细胞和胆管细胞的前体）和成熟肝细胞中表达的转基因，条件性地删除了鼠 Gata6 基因。使用胆管结扎（BDL）来模拟胆道阻塞。
Alb-Cre;Gata6 小鼠是有活力和有生育能力的。Cre 介导的 Gata6 在肝细胞中的重组对细胞结构或功能几乎没有影响。在成年 Alb-Cre;Gata6 小鼠中，大多数胆管上皮细胞中保留了 GATA6 免疫反应性，这意味着存活的胆管细胞来源于逃避了双等位基因 Cre 介导的重组的肝母细胞。尽管 GATA6 免疫反应性在胆管细胞中保留，但 Alb-cre;Gata6 小鼠有明显的胆管表型。在新生 Alb-Cre;Gata6 小鼠中，富含中性粒细胞的浸润物包围着新形成的胆管。在 37%的成年 Alb-cre;Gata6 小鼠和 0%的对照组中观察到纤维化/坏死的焦点，被认为反映了胆管形成的斑块状缺陷（p<0.05）。最值得注意的是，Alb-cre;Gata6 小鼠对 BDL 的反应发生改变，表现为存活率降低、胆管小管增殖受损、实质坏死增加、纤维化减少和门脉空间中巨噬细胞积聚增加。
GATA6 协调肝内胆管重塑，并减轻肝外胆管阻塞后的肝损伤。
