Morphogenetic competence of HNF4α-deficient mouse hepatic cells

Background/Aims To specify roles of HNF4α in mouse liver development, we have analyzed the ex vivo morphogenetic potential of HNF4α-null embryonic hepatic cells. Methods Using mice with floxed or deficiency alleles of HNF4α, hepatic cells lacking this transcription factor were explanted into primary culture and derived into cell lines. Results Contrary to behavior in vivo where HNF4α-null liver cells fail to show normal polarity and epithelialization, e18.5 hepatic cells in primary culture from mutant embryos show restoration of apical expression of tight junction protein-1 and of transcripts for E-cadherin. Clones of control and HNF4α-null cell lines were indistinguishable, even when differentiation of bile canalicular formation was induced. HNF4α-null and control cell lines showed similar potential to colonize livers of the murine ALB-uPA/SCID model of liver regeneration, but null cells formed only bile ducts and not clusters of hepatocytes. Finally, analysis of mutant embryonic livers revealed a transcriptional signature consistent with a stress response, which could underlie the morphogenetic defects observed in vivo. Conclusions We conclude that the lack of epithelialization characteristic of the HNF4α-null embryonic liver is due, at least in part, to non-cell autonomous defects, and that null cells do not suffer intrinsic defects in polarization.