Liver sinusoidal endothelium: A microenvironment-dependent differentiation program in rat including the novel junctional protein liver endothelial differentiation-associated protein-1

Authors

  • Cyrill Géraud,

    Corresponding author
    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
    • Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Mannheim, D-68135 Mannheim, Germany
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    • These authors contributed equally to this work.

    • fax: 49 (0) 621 383 3815

  • Kai Schledzewski,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
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    • These authors contributed equally to this work.

  • Alexandra Demory,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Diana Klein,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Miriam Kaus,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Francis Peyre,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Carsten Sticht,

    1. Center for Medical Research, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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  • Konstantin Evdokimov,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Shun Lu,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Astrid Schmieder,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Sergij Goerdt

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Potential conflict of interest: Nothing to report.

Abstract

Liver sinusoidal endothelium (LSEC) is a prime example of organ-specific microvascular differentiation and functions. Disease-associated capillarization of LSEC in vivo and dedifferentiation of LSEC in vitro indicate the importance of the hepatic microenvironment. To identify the LSEC-specific molecular differentiation program in the rat we used a two-sided gene expression profiling approach comparing LSEC freshly isolated ex vivo with both lung microvascular endothelial cells (LMEC) and with LSEC cultured for 42 hours. The LSEC signature consisted of 48 genes both down-regulated in LMEC and in LSEC upon culture (fold change >7 in at least one comparison); quantitative reverse-transcription polymerase chain reaction confirmation of these genes included numerous family members and signaling pathway-associated molecules. The LSEC differentiation program comprised distinct sets of growth (Wnt2, Fzd4, 5, 9, Wls, vascular endothelial growth factors [VEGFR] 1, 2, 3, Nrp2) and transcription factors (Gata4, Lmo3, Tcfec, Maf) as well as endocytosis-related (Stabilin-1/2, Lyve1, and Ehd3) and cytoskeleton-associated molecules (Rnd3/RhoE). Specific gene induction in cultured LSEC versus freshly isolated LSEC as well as LMEC (Esm-1, Aatf) and up-regulation of gene expression to LMEC levels (CXCR4, Apelin) confirmed true transdifferentiation of LSEC in vitro. In addition, our analysis identified a novel 26-kDa single-pass transmembrane protein, liver endothelial differentiation-associated protein (Leda)-1, that was selectively expressed in all liver endothelial cells and preferentially localized to the abluminal cell surface. Upon forced overexpression in MDCK cells, Leda-1 was sorted basolaterally to E-cadherin-positive adherens junctions, suggesting functional involvement in cell adhesion and polarity. Conclusion: Comparative microvascular analysis in rat identified a hepatic microenvironment-dependent LSEC-specific differentiation program including the novel junctional molecule Leda-1. HEPATOLOGY 2010

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