Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Nature. 2011 Jun 29;475(7356):390-3. doi: 10.1038/nature10263.
The location and timing of cellular differentiation must be stringently controlled for proper organ formation. Normally, hepatocytes differentiate from hepatic progenitor cells to form the liver during development. However, previous studies have shown that the hepatic program can also be activated in non-hepatic lineage cells after exposure to particular stimuli or fusion with hepatocytes. These unexpected findings suggest that factors critical to hepatocyte differentiation exist and become activated to induce hepatocyte-specific properties in different cell types. Here, by screening the effects of twelve candidate factors, we identify three specific combinations of two transcription factors, comprising Hnf4α plus Foxa1, Foxa2 or Foxa3, that can convert mouse embryonic and adult fibroblasts into cells that closely resemble hepatocytes in vitro. The induced hepatocyte-like (iHep) cells have multiple hepatocyte-specific features and reconstitute damaged hepatic tissues after transplantation. The generation of iHep cells may provide insights into the molecular nature of hepatocyte differentiation and potential therapies for liver diseases.
细胞分化的位置和时间必须严格控制，以确保器官的正常形成。通常情况下，肝细胞是从肝祖细胞分化而来，在发育过程中形成肝脏。然而，先前的研究表明，在特定刺激或与肝细胞融合后，非肝细胞谱系细胞也可以激活肝程序。这些意外的发现表明，存在对肝细胞分化至关重要的因子，并被激活以在不同的细胞类型中诱导肝细胞特异性特性。在这里，我们通过筛选十二种候选因子的作用，确定了两种转录因子（Hnf4α 加 Foxa1、Foxa2 或 Foxa3）的三个特定组合，这些组合可以将小鼠胚胎和成体成纤维细胞转化为在体外非常类似于肝细胞的细胞。诱导的肝细胞样（iHep）细胞具有多种肝细胞特异性特征，并在移植后重建受损的肝组织。iHep 细胞的产生可能为肝细胞分化的分子本质提供新的见解，并为肝脏疾病的治疗提供潜在的方法。
