Mechanisms of Liver Development: Concepts for Understanding Liver Disorders and Design of Novel Therapies

The study of liver development has significantly contributed to developmental concepts about morphogenesis and differentiation of other organs. Knowledge of the mechanisms that regulate hepatic epithelial cell differentiation has been essential in creating efficient cell culture protocols for programmed differentiation of stem cells to hepatocytes as well as developing cell transplantation therapies. Such knowledge also provides a basis for the understanding of human congenital diseases. Importantly, much of our understanding of organ development has arisen from analyses of patients with liver deficiencies. We review how the liver develops in the embryo and discuss the concepts that operate during this process. We focus on the mechanisms that control the differentiation and organization of the hepatocytes and cholangiocytes and refer to other reviews for the development of nonepithelial tissue in the liver. Much progress in the characterization of liver development has been the result of genetic studies of human diseases; gaining a better understanding of these mechanisms could lead to new therapeutic approaches for patients with liver disorders.

Abbreviations used in this paper: APC, adenomatous polyposis coli, ARF6, adenosine diphosphate–ribosylation factor 6, ATF, activating transcription factor, BMP, bone morphogenetic protein, C/EBP, CCAAT-enhancer binding protein, E, embryonic day, ER, endoplasmic reticulum, FGF, fibroblast growth factor, Fox, Forkhead box factor, HDGF, hepatoma-derived growth factor, Hes-1, homolog of hairy/enhancer of split 1, Hex, hematopoietically expressed homeobox factor, HGF, hepatocyte growth factor, HNF, hepatocyte nuclear factor, Id3, inhibitor of differentiation 3, LRH-1, liver receptor homolog 1, NF-κB, nuclear factor κB, OC, onecut factor, OSM, oncostatin M, Prox-1, Prospero-related homeobox 1, SOX9, SRY-related HMG box transcription factor 9, Tbx3, T-box transcription factor 3, TGF, transforming growth factor, TNF, tumor necrosis factor, WT1, Wilms' tumor suppressor gene, XBP-1, X-box binding protein 1, Zhx2, Zinc finger and homeoboxes factor 2