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MBC in Press, published online ahead of print May 10, 2006
Mol. Biol. Cell 10.1091/mbc.E06-01-0067

A more recent version of this article appeared on July 1, 2006
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Submitted on January 24, 2006
Revised on April 18, 2006
Accepted on April 27, 2006

Rho Kinase, Myosin-II, and p42/44 MAPK Control ECM-mediated Apical Bile Canalicular Lumen Morphogenesis in HepG2 Cells

Hilde Herrema,* Dominika Czajkowska,* Delphine Théard,* Johanna M. van der Wouden,* Dharamdajal Kalicharan,{dagger} Behnam Zolghadr,* Dick Hoekstra,* and Sven C.D. van IJzendoorn*

*Section Membrane Cell Biology and {dagger}Section Electron Microscopy, Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Monitoring Editor: Keith Mostov

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 ECM. Inhibition of Rho kinase or its target myosin-II ATPase in cells cultured on glass coverslips mimicks the morphogenic response to ECM. Consistently, stimulation of Rho kinase and subsequent myosin-II ATPase activity by lipoxygenase-controled eicosatetranoic 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.

Address correspondence to: Sven C.D. van IJzendoorn (s.c.d.van.ijzendoorn{at}med.umcg.nl)




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