Transcriptional Control: A Directional Sign at the Crossroads of Adult Hepatic Progenitor Cells' Fates

Abstract

Hepatic progenitor cells (HPCs) have a bidirectional potential to differentiate into hepatocytes and bile duct epithelial cells and constitute a second barrier to liver regeneration in the adult liver. They are usually located in the Hering duct in the portal vein region where various cells, extracellular matrix, cytokines, and communication signals together constitute the niche of HPCs in homeostasis to maintain cellular plasticity. In various types of liver injury, different cellular signaling streams crosstalk with each other and point to the inducible transcription factor set, including FoxA1/2/3, YB-1, Foxl1, Sox9, HNF4α, HNF1α, and HNF1β. These transcription factors exert different functions by binding to specific target genes, and their products often interact with each other, with diverse cascades of regulation in different molecular events that are essential for homeostatic regulation, self-renewal, proliferation, and selective differentiation of HPCs. Furthermore, the tumor predisposition of adult HPCs is found to be significantly increased under transcriptional factor dysregulation in transcriptional analysis, and the altered initial commitment of the differentiation pathway of HPCs may be one of the sources of intrahepatic tumors. Related transcription factors such as HNF4α and HNF1 are expected to be future targets for tumor treatment.

Keywords: Fate regulation.; Hepatic progenitor cells; Liver injury; Liver regeneration; Transcription factors.

Figure 1

Isolation process of “liver oval cells”.

Figure 2

Model of the adult hepatic progenitor cells niche. The interface between the end of the bile duct and the origin of the hepatic plate is called the canals of Hering. Different cell types, ECM components, and signaling streams converge here to help maintain the plasticity of adult HPCs.

Figure 3

Signal mapping of transcription factors regulating the fate of HPCs. (1) FoxA1/2 inhibits cellular energy metabolism to maintain the self-renewal. (2) Kupffer cells and Inflammatory cells release TGF-β, induce YB-1 nuclear translocation, and initiate the autophagy flow. (3) YB-1 binds to Matrix metalloproteinase genes, degrades the extracellular matrix, and promotes EMT. (4) Foxl1 is involved in the maintenance of the proliferation by crosstalk fibroblasts and hepatic stellate cells through the Hedgehog signaling pathway. (5) Macrophages acquire Wnt signals after phagocytosis of hepatocyte fragments, damaging Notch to create hepatocyte specifications. (6) Notch ligands expression in myoblasts promotes the selection of HPCs to BECs. (7) Snail inhibits hepatocyte lineage differentiation by directly inhibiting HNF4α and microRNA. (8) HNF4α restricts the migration and reduces the probability of malignant transformation. (9) HNF1α inhibits the tumor propensity.