The mesenchymal transcription factor SNAI-1 instructs human liver specification

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Hepatology

Background:

• Embryonic organogenesis relies on epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET).
• Liver development originates from epithelial endoderm, with hepatoblasts acquiring a mesenchymal phenotype to form the liver bud.
• The role of EMT in hepatic specification remains largely unknown.

Purpose of the Study:

• To investigate the phenotype of hepatoblast-like cells derived from human embryonic stem cells (hESCs).
• To elucidate the role of SNAI-1 in hepatic specification and liver development.
• To explore the dual epithelial and mesenchymal characteristics of hepatoblasts.

Main Methods:

• Generation of hepatic cells (Hep cells) from hESCs using an established protocol.
• Analysis of epithelial and mesenchymal marker expression in Hep cells and fetal livers.
• SNAI-1 knockdown experiments and chromatin immunoprecipitation (ChIP) assays.

Main Results:

• hESC-derived Hep cells display both epithelial (EpCAM, E-cadherin) and mesenchymal (vimentin, SNAI-1) markers.
• Similar dual phenotypes were observed in human and mouse fetal hepatoblasts, indicating conserved mechanisms.
• SNAI-1 knockdown impaired hepatic specification, and ChIP assays confirmed its direct binding to AFP and ALB gene promoters.

Conclusions:

• Hepatoblast-like cells derived from hESCs exhibit a conserved dual epithelial and mesenchymal phenotype.
• SNAI-1 functions unexpectedly as a transcriptional activator in hepatic specification.
• These findings provide insights into the molecular mechanisms governing liver development.