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ToxSci Advance Access published online on September 29, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh285
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 24, 2004
Accepted September 16, 2004

In Vitro Toxicology

Organ Slice Viability Extended for Pathway Characterization. An in Vitro Model to Investigate Fibrosis

Alison E. M. Vickers 1*, Muriel Saulnier 1, Elba Cruz 1, Marjolijn T. Merema 2, Kristine Rose 1, Philip Bentley 1, and Peter Olinga 2

1 Novartis Pharmaceuticals Corporation, One Health Plaza, E. Hanover, NJ 07936
2 University of Groningen, Groningen, The Netherlands

* To whom correspondence should be addressed. E-mail: vickers_alison{at}allergan.com.


  Abstract

Liver slice viability is extended to 96 hours for rat, expanding the use of this in vitro model for studying mechanisms of injury and repair, including pathways of fibrosis. The contributing factors to increased organ slice survival consist of the use of a preservation solution for liver perfusion and slice preparation, obtaining rats that are within the weight range of 250-325 g, placing a cellulose filter atop the titanium mesh roller-insert to support the slice, and maintaining the slices in an optimized culture medium which is replaced daily. The liver slices remain metabolically active, synthesizing ATP, glutathione and glycogen, and exhibit preserved organelle integrity and slice morphology. Slice preparation results in 2-cut surfaces which likely triggers a repair and regenerative response. The fibrogenic pathways are evident by the activation of stellate cells, the proliferation of myofibroblast-like cells, and an increased collagen deposition by 48 hours. Markers indicative of activated stellate cells, {alpha}-smooth muscle actin, collagen 1a1, desmin, and HSP47 are substantiated by real time-PCR. Increased staining of {alpha}-smooth muscle actin initially around the vessels and by 72-96 hr in the tissue is accompanied by increased collagen staining. Microarray gene expression revealed extracellular matrix changes with the up-regulation of cytoskeleton, filaments, collagens and actin genes; and the down-regulation of genes linked with lipid metabolism The improvements in extending liver slice survival, in conjunction with its 3-dimensional multi-cellular complexity, increases the application of this in vitro model for investigating pathways of injury and repair, and fibrosis.

Keywords: liver slices; fibrosis in vitro model.
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