Rho kinase, myosin-II, and p42/44 MAPK control extracellular matrix-mediated apical bile canalicular lumen morphogenesis in HepG2 cells

H Herrema, D Czajkowska, D Theard, JM van der Wouden, D Kalicharan, B Zolghadr, D Hoekstra, SCD Ijzendoorn*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The molecular mechanisms that regulate multicellular architecture and the development of extended apical bile canalicular lumens in hepatocytes are poorly understood. Here, we show that hepatic HepG2 cells cultured on glass coverslips first develop intercellular apical lumens typically formed by a pair of cells. Prolonged cell culture results in extensive organizational changes, including cell clustering, multilayering, and apical lumen morphogenesis. The latter includes the development of large acinar structures and subsequent elongated canalicular lumens that span multiple cells. These morphological changes closely resemble the early organizational pattern during development, regeneration, and neoplasia of the liver and are rapidly induced when cells are cultured on predeposited extracellular matrix (ECM). Inhibition of Rho kinase or its target myosin-II ATPase in cells cultured on glass coverslips mimics the morphogenic response to ECM. Consistently, stimulation of Rho kinase and subsequent myosin-II ATPase activity by lipoxygenase-controlled eicosa-tetranoic acid metabolism inhibits ECM-mediated cell multilayering and apical lumen morphogenesis but not initial apical lumen formation. Furthermore, apical lumen remodeling but not cell multilayering requires basal p42/44 MAPK activity. Together, the data suggest a role for hepatocyte-derived ECM in the spatial organization of hepatocytes and apical lumen morphogenesis and identify Rho kinase, myosin-II, and MAPK as potentially important players in different aspects of bile canalicular lumen morphogenesis. © 2006 by The American Society for Cell Biology.
Original languageEnglish
Pages (from-to)3291-3303
Number of pages13
JournalMolecular Biology of the Cell
Volume17
Issue number7
DOIs
Publication statusPublished - Jul-2006

Keywords

  • RAT HEPATOCYTE SPHEROIDS
  • LIVER DEVELOPMENT
  • HEPATIC CELLS
  • SMOOTH-MUSCLE
  • IN-VITRO
  • SUBAPICAL COMPARTMENT
  • POLARITY DEVELOPMENT
  • INTRACELLULAR SITES
  • MEMBRANE BIOGENESIS
  • ADHESION MOLECULES

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