Abstract
Our knowledge of complex pathological mechanisms underlying organ fibrosis is predominantly derived from animal studies. However, relevance of animal models for human disease is limited; therefore, an ex vivo model of human precision-cut tissue slices (PCTS) might become an indispensable tool in fibrosis research and drug development by bridging the animal–human translational gap. This study, presented as two parts, provides comprehensive characterization of the dynamic transcriptional changes in PCTS during culture by RNA sequencing. Part I investigates the differences in culture-induced responses in murine and human PCTS derived from healthy liver, kidney and gut. Part II delineates the molecular processes in cultured human PCTS generated from diseased liver, kidney and ileum. We demonstrated that culture was associated with extensive transcriptional changes and impacted PCTS in a universal way across the organs and two species by triggering an inflammatory response and fibrosis-related extracellular matrix (ECM) remodelling. All PCTS shared mRNA upregulation of IL-11 and ECM-degrading enzymes MMP3 and MMP10. Slice preparation and culturing activated numerous pathways across all PCTS, especially those involved in inflammation (IL-6, IL-8 and HMGB1 signalling) and tissue remodelling (osteoarthritis pathway and integrin signalling). Despite the converging effects of culture, PCTS display species-, organ- and pathology-specific differences in the regulation of genes and canonical pathways. The underlying pathology in human diseased PCTS endures and influences biological processes like cytokine release. Our study reinforces the use of PCTS as an ex vivo fibrosis model and supports future studies towards its validation as a preclinical tool for drug development.
Highlights
The idea of tissue slices has been around for almost a century (Warburg 1923; Krebs 1933)
Since precision-cut tissue slices (PCTS) are used as a model for fibrosis and inflammation (Westra et al 2013; Stribos et al 2017), we focused on specific canonical pathways that are related to these pathophysiological processes, including fibrosis, inflammation, apoptosis, hypoxia, etc
In Part II of this study, we investigated transcriptional changes in human PCTS by RNA sequencing
Summary
The idea of tissue slices has been around for almost a century (Warburg 1923; Krebs 1933). It was not until 1980, when Krumdieck et al (1980) developed a tissue slicer that enabled cutting of thin slices with precise thickness, the Emilia Bigaeva and Emilia Gore contributed to this work. Extended author information available on the last page of the article tissue slice technique received renewed attention. Precisioncut tissue slices (PCTS) capture the complex organotypic three-dimensional cellular structure, as each slice retains all cell types present in their original tissue-matrix configuration (de Graaf et al 2007)
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