In this review, we focus on the differentiating strategies of human stem cells into liver lineage, and especially on the effects of cytokines and gene expression during hepatic differentiation. The survey of previously published papers discloses that the protocols KU-60019 supplier that mimic the liver developmental process seem to be effective in obtaining functional hepatocytes. The hepatic differentiation seems to be composed of three steps: differentiation

to endoderm, hepatoblast formation and hepatocyte maturation. The effective protocols may depend on the inductive potentials of each step during hepatic differentiation, and finally leading to the formation of functional hepatocytes. THE LIVER DEVELOPS from the definitive endoderm epithelium of the

embryonic foregut.8 Development of the fate maps of the Xenopus tadpole gut disclosed that liver arises from lateral domains of endoderm in the developing ventral foregut.9 learn more The lateral liver domains contribute to a liver bud from embryonic days 8.5–9.5 (E8.5–9.5).8 The dorsal domain of the endoderm also develops a pancreatic bud. The interactions with cardiac mesoderm are essential for the liver to develop from the foregut endoderm.10 The cardiac mesoderm, which is specified at E7.5, induces the hepatic endoderm by the 7–8 somite stage in the mouse.11 At the time of hepatic induction, the cardiac mesoderm secretes FGF1 and FGF2.12 Fibroblast growth factor (FGF) signals from the cardiac mesoderm are necessary and sufficient to induce

a hepatic fate within the endoderm. The septum transversum mesenchyme is also necessary for hepatic specification.13 The septum transversum defines the midgut cavity around the liver after the gut tube closes off by E9.5 oxyclozanide in the mouse.10 The early septum transversum mesenchyme cells produce bone morphogenic proteins (BMPs) 2, 4 and 7.14 It has been also shown that Noggin, an inhibitor of BMP signaling, prevented hepatic induction by cardiac mesoderm or FGF4.13 Addition of BMPs 2, 4 and 7, but not other BMPs, to noggin-inhibited explants efficiently restored the hepatic induction properties of cardiac/FGF signaling.13 However, BMP signaling to the endoderm was insufficient in the absence of cardiac mesoderm, suggesting that the liver is induced in the endoderm by convergent FGF and BMP signaling from the cardiac mesoderm and the septum transversum mesenchyme.3 BMP signaling maintains the endodermal expression of GATA4,13 which is required for ventral foregut endoderm development.10,15 BMP signaling from the septum transversum mesenchyme can be considered to promote the competence of the endoderm to respond to the FGF signal from the cardiac mesoderm.10 At rodent E9.0–9.5, cells start to massively proliferate and bud into the stromal environment of the septum tranversum mesenchyme.3 The hepatic epithelial specified cells are referred to as bipotent hepatoblasts (GATA4+, HNF4α+, HNF6+, AFP+, albumin+, CK17+ and CK19+).