Temporal transcriptomic changes in canine liver slices compared to native liver (1148.3)

Abstract

Precision cut tissue slices retain the multicellular, structural, and functional features of the original organ and therefore offer a potentially more relevant approach to interrogate toxicity and pharmacology. However, limited data are available regarding transcriptomic changes occurring after slicing and in culture. Here, global mRNA profiles of canine liver slices immediately after preparation (0 h) and up to 48 h in culture were evaluated relative to whole liver. Liver slices from a male beagle dog were prepared and cultured at 37°C in an O2 rich atmosphere for 0, 24 and 48 h. Integrity of the slices was monitored using routine viability markers. Total RNA was isolated for analysis on Affymetrix canine genome microarrays. At 0 h, only minor perturbation of the transcriptome was apparent, indicating similarity to liver at the transcriptional level. After 24 to 48 h, ~8300 expression changes were observed. At 0 h, mRNA levels of phase I/II drug metabolizing enzymes were unchanged, but thereafter declined. Apoptotic signaling and proteasome mRNAs increased after 24 h, but not at 0 h, suggesting minor early stress signals. After 24 h, fibrosis pathway activation was evident with substantial increases in IL‐6 and IL‐8 mRNA. Unlike primary hepatocytes, a test substance can be incubated in slices at 0 h, allowing for the retention of an organ‐like molecular environment and thus offering advantages compared to monolayers.Grant Funding Source: Supported by AbbVie