Signalling pathways and transcriptional regulators orchestrating liver development and cancer

Abstract

Liver development is controlled by key signals and transcription factors that drive cell proliferation, migration, differentiation and functional maturation. In the adult liver, cell maturity can be perturbed by genetic and environmental factors that disrupt hepatic identity and function. Developmental signals and fetal genetic programmes are often dysregulated or reactivated, leading to dedifferentiation and disease. Here, we highlight signalling pathways and transcriptional regulators that drive liver cell development and primary liver cancers. We also discuss emerging models derived from pluripotent stem cells, 3D organoids and bioengineering for improved studies of signalling pathways in liver cancer and regenerative medicine.

Loss of liver function in chronic liver disease: An identity crisis

“…During embryonic development liver organogenesis arises from the foregut endoderm, a region from which pancreas progenitors are also derived. Signals from adjacent cardiac mesoderm and the septum transversum mesenchyme (STM), particularly fibroblast growth factor (FGF) and bone morphogenic protein (BMP) respectively, suppress the pancreas program and, together with Nodal signalling, specify the hepatic fate with the emergence of hepatoblasts, the liver parenchymal progenitor cells [2,8]. The expansion of the hepatoblast pool is to a great extent regulated by BMP, FGF, WNT and transforming growth factor  (TGF) signalling from the nearby endothelium and the STM [8].…”

“…This gene expression signature is progressively established from early hepatic development through cell-to-cell signalling and a network of key transcription factors (TFs) and their activation or repression complexes, that shape up liver-specific gene expression [6]. After birth, an increasingly complex set of cross-regulated TFs, plus signalling systems such as WNT and Notch, and splicing regulators (SR), define the liver zonal architecture and consolidate mature hepatocellular function [2,[6][7][8]]. An intricate system of signals, TFs and epigenetic mechanisms secure the preservation of the liverspecific gene expression pattern (i.e.…”

Comparative Transcriptome Analysis Provides Novel Molecular Events for the Differentiation and Maturation of Hepatocytes during the Liver Development of Zebrafish

“…During the subsequent growth phase, the size, shape, and placement of liver began to extend across the midline ventral to esophagus and forms the architecture [ 54 ]. Studies in mammals indicated that liver development began with the appearance of liver buds, to the formation of liver progenitor cells, followed by the proliferation, differentiation, and migration of hepatic progenitor cells, and finally to the formation of liver, undergoing a complex process of cell signal regulation [ 12 , 21 , 53 ]. Furthermore, extrinsic signaling pathways and cell-autonomous transcription factors tightly regulate liver organogenesis [ 55 ].…”

“…The liver development process involved in many pathways, such as bone morphogenetic protein (BMP), transforming growth factor β (TGFβ), Wnt, and Hippo and Notch signaling pathways in mammals [ 21 ]. The Wnt signaling pathway tightly controls embryogenesis, including hepatobiliary development, maturation, and zonation, and it can increase glucose metabolism in hepatocellular carcinoma cells [ 12 , 57 ].…”

“…Wnt1 and Lhx2 deletion embryos showed an ectopic activation state with ECM deposition, fibrosis, and the smaller liver phenotype due to hepatocyte proliferation abnormalities [ 20 ]. Other factors that promote hepatocyte maturation include the cytokine oncostatin M (OSM), hepatocyte growth factor (HGF), and the continuing inhibition of Notch and TGF signaling [ 21 , 22 ].…”