Human precision-cut tissue slices as a tool to study fibrosis and the efficacy of antifibrotic compounds

Fibrosis is a common endpoint of a multiplicity of chronic diseases resulting in scarring and loss of organ function. To improve and accelerate antifibrotic drug discovery, there is an urgent need for reliable and reproducible human in vitro methods that also include the cellular diversity that epitomize specific organs. The objective of our study was to investigate fibrogenesis in precision-cut tissue slices (PCTS) from human liver and kidney. Moreover, we strove to elucidate the effect of imatinib - a promising antifibrotic compound in rat - in the early stages of liver fibrosis. PCTS were successfully prepared from human livers and kidneys, and cultured up to 72 hours. Viability of PCTS was assessed by the ATP content of the slices. Furthermore, gene expression of several fibrosis markers was determined. The antifibrotic effect of imatinib was studied at the maximal non-toxic concentrations. Both liver and renal PCTS were viable up to 72 hours. Furthermore, after 48 hours of incubation, the early onset of fibrosis was observed in liver PCTS, as demonstrated by an increased expression of Pro-Collagen 1A1 and Heat Shock Protein 47. Moreover, treatment with imatinib for 48 hours did neither impact the gene expression of fibrosis markers nor the protein expression of collagen I in human liver PCTS. Which is in stark disparity to the antifibrotic effects observed in animal models. The gene expression profile of renal PCTS during incubation is currently being evaluated. Thus, human PCTS can be used to study the onset of fibrosis, are promising models to test the efficacy of antifibrotic compounds and can reveal species differences in fibrosis