Morphogenetic competence of HNF4α-deficient mouse hepatic cells

JOURNAL OF HEPATOLOGY

卷:49

Article

Hayhurst, Graham P.¹  Strick-Marchand, Helene¹  Mulet, Celine¹  Richard, Anne-Francoise^1,5  Morosan, Serban^2,3,4,6  Kremsdorf, Dina^2,3,4  Weiss, Mary C.^1,2 

[1] Inst Pasteur, CNRS, Unite Rech Associce 2578, Unite Genet Differenciat, Paris, France

[2] CHU Necker, INSERM, U845, F-75015 Paris, France

[3] Inst Pasteur, Dept Virol, Paris, France

[4] Univ Paris 05, CHU Necker, Paris, France

[5] Inst Cochin Genet Mol, F-75014 Paris, France

[6] INSERM, Fac Med Pierre Marie Curie, Ctr Expt Fonctionnelle, Paris, France

关键词: hepatocytes;    cholangiocytes;    liver repopulation;    cell polarization;    stress response;   

DOI  :  10.1016/j.jhep.2008.04.024

来源: Elsevier

【 摘 要 】

Background/Aims: To specify roles of HNF4 alpha in mouse liver development, we have analyzed the ex vivo morphogenetic potential of HNF4 alpha-null embryonic hepatic cells. Methods: Using mice with fluxed or deficiency alleles of HNF4 alpha, hepatic cells lacking this transcription factor were explanted into primary culture and derived into cell lines. Results: Contrary to behavior in vivo where HNF4 alpha-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 HNF4 alpha-null cell lines were indistinguishable, even when differentiation of bile canalicular formation was induced. HNF4 alpha-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 HNF4 alpha-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. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

Free