Bisgaard Hanne Cathrine, Holmskov Uffe, Santoni-Rugiu Eric, Nagy Peter, Nielsen Ole, Ott Peter, Hage Ester, Dalhoff Kim, Rasmussen Lene Juel, Tygstrup Niels
Department of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Am J Pathol. 2002 Oct;161(4):1187-98. doi: 10.1016/S0002-9440(10)64395-7.
The regenerative capacity of mammalian adult liver reflects the ability of a number of cell populations within the hepatic lineage to take action. Limited information is available regarding factors and mechanisms that determine the specific lineage level at which liver cells contribute to liver repair as well as the fate of their progeny in the hostile environment created by liver injury. In the present study, we attempted to identify novel molecules preferentially involved in liver regeneration by recruitment of transit-amplifying, ductular (oval) cell populations. With a subtractive cDNA library screening approach, we identified 48 enriched, nonredundant gene products associated with liver injury and oval cell proliferation in the adult rat liver. Of these, only two, namely alpha-fetoprotein and a novel transcript with high homology to human DMBT1 (deleted in malignant brain tumor 1), were specifically associated with the emergence of ductular (oval) cell populations in injured liver. Subsequent cloning and characterization of the rat DMBT1 homologue revealed a highly inducible expression in ductular reactions composed of transit-amplifying ductular (oval) cells, but not in ductular reactions after ligation of the common bile duct. In human liver diseases, DMBT1 was expressed in ductular reactions after infection with hepatitis B and acetaminophen intoxication, but not in primary biliary cirrhosis, primary sclerosing cholangitis, and obstruction of the large bile duct. The expression heterogeneity in ductular reactions and multiple functions of DMBT1 homologues point to intriguing roles in regulating not only tissue repair but also fate decision and differentiation paths of specific cell populations in the hepatic lineage.
哺乳动物成年肝脏的再生能力反映了肝谱系中多个细胞群体采取行动的能力。关于决定肝细胞在肝脏修复中发挥作用的特定谱系水平的因素和机制，以及它们的子代在肝损伤所造成的恶劣环境中的命运，目前可用信息有限。在本研究中，我们试图通过募集过渡扩增性、小胆管（卵圆）细胞群体来鉴定优先参与肝脏再生的新分子。采用消减cDNA文库筛选方法，我们在成年大鼠肝脏中鉴定出48种与肝损伤和卵圆细胞增殖相关的富集且非冗余的基因产物。其中，只有两种，即甲胎蛋白和一种与人类DMBT1（恶性脑肿瘤1中缺失）具有高度同源性的新转录本，与损伤肝脏中小胆管（卵圆）细胞群体的出现特异性相关。随后对大鼠DMBT1同源物的克隆和表征显示，其在由过渡扩增性小胆管（卵圆）细胞组成的小胆管反应中高度可诱导表达，但在胆总管结扎后的小胆管反应中不表达。在人类肝脏疾病中，DMBT1在乙型肝炎感染和对乙酰氨基酚中毒后的小胆管反应中表达，但在原发性胆汁性肝硬化、原发性硬化性胆管炎和大胆管梗阻中不表达。DMBT1同源物在小胆管反应中的表达异质性及其多种功能表明，它不仅在调节组织修复方面，而且在调节肝谱系中特定细胞群体的命运决定和分化途径方面都发挥着有趣的作用。
