Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Development. 2014 Feb;141(3):538-47. doi: 10.1242/dev.099481.
The liver has multiple functions that preserve homeostasis. Liver diseases are debilitating, costly and often result in death. Elucidating the developmental mechanisms that establish the liver's architecture or generate the cellular diversity of this organ should help advance the prevention, diagnosis and treatment of hepatic diseases. We previously reported that migration of early hepatic precursors away from the gut epithelium requires the activity of the homeobox gene Prox1. Here, we show that Prox1 is a novel regulator of cell differentiation and morphogenesis during hepatogenesis. Prox1 ablation in bipotent hepatoblasts dramatically reduced the expression of multiple hepatocyte genes and led to very defective hepatocyte morphogenesis. As a result, abnormal epithelial structures expressing hepatocyte and cholangiocyte markers or resembling ectopic bile ducts developed in the Prox1-deficient liver parenchyma. By contrast, excessive commitment of hepatoblasts into cholangiocytes, premature intrahepatic bile duct morphogenesis, and biliary hyperplasia occurred in periportal areas of Prox1-deficient livers. Together, these abnormalities indicate that Prox1 activity is necessary to correctly allocate cell fates in liver precursors. These results increase our understanding of differentiation anomalies in pathological conditions and will contribute to improving stem cell protocols in which differentiation is directed towards hepatocytes and cholangiocytes.
肝脏具有多种维持内稳态的功能。肝脏疾病使人虚弱，代价高昂，且常导致死亡。阐明建立肝脏结构或产生该器官细胞多样性的发育机制，应有助于推进肝脏疾病的预防、诊断和治疗。我们之前曾报道，早期肝前体细胞从肠道上皮迁移需要同源盒基因 Prox1 的活性。在这里，我们表明 Prox1 是肝发生过程中细胞分化和形态发生的新型调节因子。在双潜能肝母细胞中敲除 Prox1 会显著降低多种肝细胞基因的表达，并导致非常严重的肝细胞形态发生缺陷。结果，在 Prox1 缺陷的肝实质中，异常表达肝细胞和胆管细胞标志物的上皮结构或类似于异位胆管的结构发育。相比之下，Prox1 缺陷肝脏的门脉周围区域会发生肝母细胞过度向胆管细胞分化、过早的肝内胆管形态发生和胆管增生。这些异常共同表明，Prox1 活性对于正确分配肝前体细胞的细胞命运是必要的。这些结果增加了我们对病理条件下分化异常的理解，并将有助于改进将分化定向为肝细胞和胆管细胞的干细胞方案。
