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ToxSci Advance Access originally published online on September 29, 2004
Toxicological Sciences 2004 82(2):534-544; doi:10.1093/toxsci/kfh285
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Toxicological Sciences vol. 82 no. 2 © Society of Toxicology 2004; all rights reserved.

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

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

* Novartis Pharmaceuticals Corporation, One Health Plaza, E. Hanover, New Jersey 07936 and {dagger} University of Groningen, Groningen, The Netherlands

Received June 24, 2004; accepted September 16, 2004

Liver slice viability is extended to 96 h 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 adenosine triphosphate (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 h. 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 h 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 three-dimensional multi-cellular complexity, increases the application of this in vitro model for investigating pathways of injury and repair, and fibrosis.

Key Words: liver slices; fibrosis in vitro model.


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