Liver development starts after the formation of the endoderm during gastrulation, more specifically in the foregut. The first transcription factors that confer hepatic competence are forkhead-box protein A (FOXA) and Gata binding protein (GATA) [10, 11]. Both factors are expressed in the ventral foregut endoderm even before albumin (ALB) is expressed. Fibroblast growth factor (FGF), BMP (Bone morphogenetic protein) and Wnt are expressed and secreted by the mesoderm adjacent to the ventral foregut endoderm (cardiac mesoderm and septum transversum) and are to date identified as the only early hepatic inducing signals. All three factors stimulate differentiation of endodermal cells into proliferating hepatoblasts that will lead to endodermal thickening (= the liver bud) [13-15].
Hepatoblasts are bipotential stem cells that express a-fetoprotein, transthyretin and hepatocyte nuclear factor 4a (HNF4a). Their expansion is regulated by key signalling pathways, like hepatocyte growth factor (HGF), Retinoic acid, BMP and FGF signalling. Hepatoblast are identified as Dlk-1+EpCAM+ cells and are capable of differentiating into hepatocytes or cholangiocytes . If one hepatoblast is committed to the cholangiocyte or hepatocyte lineage, they undergo maturation by expressing lineage-specific gene profiles, morphological changes and changes in physiological functions. Hepatoblasts located around the portal vein are committed to cholangiocytes by activation of Notch and TGFb signals from the ductal plates [17, 18]. These immature cholangiocytes already express cholangiocyte markers like SOX9, OPN and EpCAM . Immature hepatocytes are characterised by expressing different transcription factors such as FoxA1/2, HNF1a/b, HNF4a and HNF6 . Their maturation is regulated by oncostatin M (OSM), HGF and transcription factor C/EBPa [21, 22]. Newly-formed hepatocytes from hepatoblasts are organised as cord-like structure. These cords consist of a single layer of hepatocytes that are separated from other cords by LSECs and the space of Disse. The formation of these cords lead to hepatocyte polarization, an important aspect to hepatocyte maturation, as both sides are located in a different environment. Wnt/b-catenin crusial role in this step. Its signalling is most active in pericentral developing hepatocytes and gradually decreases its activity towards periportal hepatocytes . Specialization of location-specific hepatocytes allows the liver to perform inverse metabolic functions (like glucolysis and gluconeogenesis) within the same organ . Non-epithelial liver cells have a different origin. Hepatic vascularization starts around the interception of the liver primordium where it invades the hepatic bud during its growth . These endothelial cells form a complex capillary network containing primitive sinusoidal structures. Sinusoids are surrounded by extracellular matrix produced by HSCs. Their maturation is further stimulated by vascular endothelial growth factor (VEGF), produced by developing hepatoblasts . HSCs are derived from mesothelial and submesothelial cells during liver development and play a major role in morphogenesis of the liver by excreting Wnt9a, HGF and other mitotic factors for hepatoblasts and hepatocytes [26-28]. Kupffer cells are resident macrophages in the liver which appear first in the yolk sac during embryonic development. They derive from macrophages via the umbilical veins and left vitelline vein and become F4/80 positive around day 11 of gestation in mice [29, 30].
10. Cirillo, L.A., F.R. Lin, I. Cuesta, D. Friedman, M. Jarnik, and K.S. Zaret, Opening of
compacted chromatin by early developmental transcription factors HNF3 (FoxA)
and GATA-4. Mol Cell, 2002
11. Cirillo, L.A., C.E. McPherson, P. Bossard, K. Stevens, S. Cherian, E.Y. Shim, K.L.
Clark, S.K. Burley, and K.S. Zaret, Binding of the winged-helix transcription factor
HNF3 to a linker histone site on the nucleosome. EMBO J, 1998.
12. Bossard, P. and K.S. Zaret, GATA transcription factors as potentiators of gut
endoderm differentiation. Development, 1998
13. Ober, E.A., H. Verkade, H.A. Field, and D.Y. Stainier, Mesodermal Wnt2b signalling
positively regulates liver specification. Nature, 2006. 10.1038/nature04888.
14. Doerks, T., R.R. Copley, J. Schultz, C.P. Ponting, and P. Bork, Systematic
identification of novel protein domain families associated with nuclear functions.
Genome Res, 2002. 10.1101/.
15. Serls, A.E., S. Doherty, P. Parvatiyar, J.M. Wells, and G.H. Deutsch, Different
thresholds of fibroblast growth factors pattern the ventral foregut into liver and
lung. Development, 2005. 10.1242/dev.01570.
16. Tanaka, M., M. Okabe, K. Suzuki, Y. Kamiya, Y. Tsukahara, S. Saito, and A.
Miyajima, Mouse hepatoblasts at distinct developmental stages are characterized
by expression of EpCAM and DLK1: drastic change of EpCAM expression during
liver development. Mech Dev, 2009. S0925-4773(09)00076-8 [pii]
17. Tanimizu, N. and A. Miyajima, Notch signaling controls hepatoblast differentiation
by altering the expression of liver-enriched transcription factors. J Cell Sci, 2004.
18. Clotman, F., P. Jacquemin, N. Plumb-Rudewiez, C.E. Pierreux, P. Van der Smissen,
H.C. Dietz, P.J. Courtoy, G.G. Rousseau, and F.P. Lemaigre, Control of liver cell fate
decision by a gradient of TGF beta signaling modulated by Onecut transcription
factors. Genes Dev, 2005. 10.1101/gad.340305.
19. Antoniou, A., P. Raynaud, S. Cordi, Y. Zong, F. Tronche, B.Z. Stanger, P. Jacquemin,
C.E. Pierreux, F. Clotman, and F.P. Lemaigre, Intrahepatic bile ducts develop
according to a new mode of tubulogenesis regulated by the transcription factor
SOX9. Gastroenterology, 2009
20. Si-Tayeb, K., F.P. Lemaigre, and S.A. Duncan, Organogenesis and Development of
the Liver. Developmental Cell, 2010. 10.1016/j.devcel.2010.01.011.
21. Kamiya, A., T. Kinoshita, Y. Ito, T. Matsui, Y. Morikawa, E. Senba, K. Nakashima, T.
Taga, K. Yoshida, T. Kishimoto, and A. Miyajima, Fetal liver development requires a
paracrine action of oncostatin M through the gp130 signal transducer. Embo
Journal, 1999. DOI 10.1093/emboj/18.8.2127.
22. Wang, N.D., M.J. Finegold, A. Bradley, C.N. Ou, S.V. Abdelsayed, M.D. Wilde, L.R.
Taylor, D.R. Wilson, and G.J. Darlington, Impaired energy homeostasis in C/EBP
alpha knockout mice. Science, 1995
23. Torre, C., C. Perret, and S. Colnot, Transcription dynamics in a physiological
process: beta-catenin signaling directs liver metabolic zonation. Int J Biochem Cell
Biol, 2011. 10.1016/j.biocel.2009.11.004.
24. Matsumoto, K., H. Yoshitomi, J. Rossant, and K.S. Zaret, Liver organogenesis
promoted by endothelial cells prior to vascular function. Science, 2001.
25. Nonaka, H., M. Tanaka, K. Suzuki, and A. Miyajima, Development of murine hepatic
sinusoidal endothelial cells characterized by the expression of hyaluronan
receptors. Dev Dyn, 2007. 10.1002/dvdy.21227.
26. Shin, D. and S.P.S. Monga, Cellular and Molecular Basis of Liver Development.
27. Matsumoto, K., R. Miki, M. Nakayama, N. Tatsumi, and Y. Yokouchi, Wnt9a
secreted from the walls of hepatic sinusoids is essential for morphogenesis,
proliferation, and glycogen accumulation of chick hepatic epithelium. Dev Biol,
28. Onitsuka, I., M. Tanaka, and A. Miyajima, Characterization and functional analyses
of hepatic mesothelial cells in mouse liver development. Gastroenterology, 2010.
29. Nguyen-Lefebvre, A.T. and A. Horuzsko, Kupffer Cell Metabolism and Function. J
Enzymol Metab, 2015
30. Takahashi, K., F. Yamamura, and M. Naito, Differentiation, Maturation, and
Proliferation of Macrophages in the Mouse Yolk Sac: A Light-Microscopic, Enzyme-
Cytochemical, Immunohistochemical, and Ultrastructural Study. Journal of
Leukocyte Biology, 1989. 10.1002/jlb.45.2.87.