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The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer

Gene Therapy volume 15, pages 1193–1199 (2008)Cite this article

Abstract

Fenestrae allow the passage of gene transfer vectors from the sinusoidal lumen to the surface of hepatocytes. We have previously shown that the diameter of fenestrae correlates with species and strain differences of transgene expression following intravenous adenoviral transfer. In the current study, we demonstrate that the diameter of fenestrae in humans without liver pathology is 107±1.5 nm. This is similar to the previously reported diameter in New Zealand White (NZW) rabbits (103±1.3 nm) and is significantly smaller than in C57BL/6 mice (141±5.4 nm) and Sprague–Dawley rats (161±2.7 nm). We show that the diameter of fenestrae in one male NZW rabbit and its offspring characterized by a more than 50-fold increase of transgene expression after adenoviral gene transfer is significantly (113±1.5 nm; P<0.001) larger than in control NZW rabbits. In vitro filtration experiments using polycarbonate filters with increasing pore sizes demonstrate that a relatively small increment of the diameter of pores potently enhances passage of adenoviral vectors, consistent with in vivo data. In conclusion, the small diameter of fenestrae in humans is likely to be a major obstacle for hepatocyte transduction by adenoviral vectors.

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Acknowledgements

This work was supported by Grant G.0322.06N of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. The Center for Molecular and Vascular Biology is supported by the Excellentiefinanciering KU Leuven (EF/05/013). Frank Jacobs is a Research Assistant of the Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen. We thank H Duimel, J Hendrix and Z Zhang for excellent technical assistance.

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Author notes

  1. E Wisse and F Jacobs: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, EM Unit, University of Maastricht, Maastricht, The Netherlands

    E Wisse & P Frederik

  2. Department of Molecular and Cellular Medicine, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

    F Jacobs & B De Geest

  3. Department of Abdominal Surgery, University of Leuven, Leuven, Belgium

    B Topal

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  1. E Wisse
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  2. F Jacobs
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  4. P Frederik
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  5. B De Geest
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Correspondence to B De Geest.

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Wisse, E., Jacobs, F., Topal, B. et al. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer. Gene Ther 15, 1193–1199 (2008). https://doi.org/10.1038/gt.2008.60

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  • DOI: https://doi.org/10.1038/gt.2008.60

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