Ex vivo fibrosis research: 5 mm closer to human studies

Tissue repair is essential for the survival of any organism. However, when physiological repair processes fail, a pathological condition known as fibrosis arises, which compromises tissue architecture and ultimately results in loss of organ function. Despite decades of research that significantly advanced our understanding of the underlying mechanisms of organ fibrosis, effective antifibrotic therapies currently do not exist. Biomedical research devoted to treat human diseases has, to date, resulted in limited clinical success when relying on conventional culture systems and animal models. The search for new, predictive and translational preclinical models sets the objective of this thesis, in which we explored the use of precision-cut tissue slices (PCTS), three-dimensional mini-organs, in fibrosis research. When prepared from human tissues, these thin slices, only 5 mm in diameter, eliminate the need for animal-to-human extrapolation and, along with animal tissue slices, significantly contribute to the refinement, reduction and replacement of animal experiments (3Rs). This thesis encompasses three different parts: 1) extensive characterization of the molecular processes in the PCTS culture system; 2) suitability of PCTS as preclinical drug screening tool with high predictivity and clinical relevance; and 3) optimization of PCTS culture conditions to improve tissue longevity. This work emphasizes the value of using human tissue for advancing fibrosis research and drug development. Beyond conventional preclinical tools, thin tissue slices represent a major step towards understanding and treating human fibrosis.