Sergi C, Kahl P, Otto H F
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
Am J Pathol. 2000 May;156(5):1589-98. doi: 10.1016/S0002-9440(10)65031-6.
In the developing liver, the complete or partial persistence of the primitive double-layered cylinder of biliary-type cells that surrounds the branches of portal vein and its mesenchyme gives origin to portal tracts with an increased number of bile duct structures. The term "ductal plate malformation of the liver" was coined to label the insufficient remodeling of the primitive intrahepatic biliary system. Meckel syndrome is an autosomal recessive inherited disease characterized by occipital encephalocele, postaxial polydactyly, diffuse cystic renal dysplasia, and malformation of the ductal plate of the liver. We studied 52 fetuses with Meckel syndrome from five German centers (Berlin, Freiburg, Heidelberg, Mainz, and Marburg). Analysis of apoptosis and cell proliferation (Ki-67) was performed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry in the liver of 24 normal fetuses of different gestational ages (14-38 weeks of gestation) and in 14 fetuses with Meckel syndrome (17-38 weeks of gestation). The expression of two apoptosis-related proteins, Fas (a transmembrane cell surface protein involved in the apoptosis) and Bcl-2 (an anti-apoptotic protein), was studied by immunohistochemistry in the liver of 11 normal fetuses of different gestational ages (14-40 weeks of gestation) and in 40 fetuses with Meckel syndrome (16-38 weeks of gestation). In control fetuses, apoptosis rate and cell proliferation were high in the remodeling ductal plate and moderate in the ductal plate and in remodeled bile ducts. During gestation, expression of Fas and Bcl-2 decreased and increased, respectively. The malformed ductal plates in the fetal livers with Meckel syndrome showed a marked decrease in the apoptotic rate and Fas expression and an increase in proliferative activity and Bcl-2 expression in comparison with control fetuses. Furthermore, by linear regression analysis, we found that both proliferation activity and apoptosis rate in the ductal plate malformation of fetuses with Meckel syndrome were practically constant along the gestation. These results, which represent the first systematic study of apoptosis in ductal plate malformation of the liver, indicate that 1) animals harboring the gene defect of Meckel syndrome could be a good model for the study of the abnormal development of the primitive intrahepatic biliary system, 2) a decreased cell turnover occurs in the ductal plate malformation of fetuses with Meckel syndrome, and 3) the increase of Bcl-2 expression contributes to the pathogenesis of the lack of remodeling of ductal plate of the liver in Meckel syndrome.
在发育中的肝脏中，围绕门静脉分支及其间充质的双层胆管样细胞原始圆柱体的完全或部分持续存在会导致门管区胆管结构数量增加。“肝脏导管板畸形”这一术语用于描述原始肝内胆管系统重塑不足的情况。梅克尔综合征是一种常染色体隐性遗传病，其特征为枕部脑膨出、轴后多指畸形、弥漫性多囊性肾发育不良以及肝脏导管板畸形。我们研究了来自德国五个中心（柏林、弗莱堡、海德堡、美因茨和马尔堡）的52例患有梅克尔综合征的胎儿。通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法（TUNEL）和免疫组织化学，对24例不同孕周（妊娠14 - 38周）的正常胎儿肝脏以及14例患有梅克尔综合征的胎儿（妊娠17 - 38周）肝脏进行了凋亡和细胞增殖（Ki - 67）分析。通过免疫组织化学研究了11例不同孕周（妊娠14 - 40周）的正常胎儿肝脏以及40例患有梅克尔综合征的胎儿（妊娠16 - 38周）肝脏中两种凋亡相关蛋白Fas（一种参与凋亡的跨膜细胞表面蛋白）和Bcl - 2（一种抗凋亡蛋白）的表达。在对照胎儿中，重塑导管板中的凋亡率和细胞增殖较高，而导管板和重塑胆管中的凋亡率和细胞增殖则中等。在妊娠期间，Fas和Bcl - 2的表达分别下降和上升。与对照胎儿相比，患有梅克尔综合征的胎儿肝脏中畸形导管板的凋亡率和Fas表达明显降低，增殖活性和Bcl - 2表达增加。此外，通过线性回归分析，我们发现患有梅克尔综合征的胎儿导管板畸形中的增殖活性和凋亡率在整个妊娠过程中实际上是恒定的。这些结果是对肝脏导管板畸形中凋亡的首次系统性研究，表明：1）携带梅克尔综合征基因缺陷的动物可能是研究原始肝内胆管系统异常发育的良好模型；2）患有梅克尔综合征的胎儿导管板畸形中细胞更新减少；3）Bcl - 2表达的增加促成了梅克尔综合征中肝脏导管板缺乏重塑的发病机制。
