Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, Japan.
J Cell Sci. 2013 Nov 15;126(Pt 22):5239-46. doi: 10.1242/jcs.133082. Epub 2013 Sep 17.
In developing organs, epithelial tissue structures are mostly developed by the perinatal period. However, it is unknown whether epithelial cells are already functionally mature and whether they are fixed in their lineage. Here we show that epithelial cells alter their plasticity during postnatal development by examining the differentiation potential of epithelial cell adhesion molecule (EpCAM)(+) cholangiocytes (biliary epithelial cells) isolated from neonatal and adult mouse livers. We found that neonatal cholangiocytes isolated from 1-week-old liver converted into functional hepatocytes in the presence of oncostatin M and Matrigel®. In contrast, neither morphological changes nor expression of hepatocyte markers were induced in adult cholangiocytes. The transcription factors hepatocyte nuclear factor 4α and CCAAT/enhancer binding protein α (C/EBPα), which are necessary for hepatocytic differentiation, were induced in neonatal cholangiocytes but not in adult cells, whereas grainyhead-like 2 (Grhl2) and hairy-enhance of slit 1 (Hes1), which are implicated in cholangiocyte differentiation, were continuously expressed in adult cells. Overexpression of C/EBPα and Grhl2 promoted and inhibited hepatocytic differentiation, respectively. Furthermore, adult cholangiocytes formed a monolayer with higher barrier function than neonatal ones did, suggesting that cholangiocytes are still in the process of epithelial maturation even after forming tubular structures during the neonatal period. Taken together, these results suggest that cholangiocytes lose plasticity to convert into hepatocytes during epithelial maturation. They lose competency to upregulate hepatocytic transcription factors and downregulate cholagiocytic ones under conditions inducing hepatocytic differentiation. Our results suggest that a molecular machinery augmenting epithelial integrity limits lineage plasticity of epithelial cells.
在发育器官中，上皮组织结构大多在围产期发育形成。然而，尚不清楚上皮细胞是否已经具有功能成熟性，以及它们是否固定在其谱系中。在这里，我们通过检查从新生和成年小鼠肝脏中分离的上皮细胞黏附分子（EpCAM）（+）胆管细胞（胆管上皮细胞）的分化潜能，表明上皮细胞在出生后发育过程中改变了其可塑性。我们发现，在存在oncostatin M 和 Matrigel®的情况下，从 1 周龄肝脏分离的新生胆管细胞可转化为功能性肝细胞。相比之下，成年胆管细胞既未诱导形态变化，也未诱导肝细胞标记物的表达。肝细胞核因子 4α和 CCAAT/增强子结合蛋白α（C / EBPα）的转录因子，是肝细胞分化所必需的，在新生胆管细胞中诱导，但在成年细胞中未诱导，而 Grainyhead-like 2（Grhl2）和 hairy-enhance of slit 1（Hes1），其参与胆管细胞分化，在成年细胞中持续表达。C / EBPα和 Grhl2 的过表达分别促进和抑制肝细胞分化。此外，成年胆管细胞形成的单层具有比新生胆管细胞更高的屏障功能，这表明胆管细胞即使在新生儿期形成管状结构后仍处于上皮成熟过程中。总之，这些结果表明胆管细胞在上皮成熟过程中丧失了转化为肝细胞的可塑性。它们在诱导肝细胞分化的条件下丧失了上调肝细胞转录因子和下调胆管细胞转录因子的能力。我们的结果表明，增强上皮完整性的分子机制限制了上皮细胞的谱系可塑性。
