Innovative three-dimensional models for understanding mechanisms underlying lung diseases: powerful tools for translational research

Abstract

Chronic lung diseases result from alteration and/or destruction of lung tissue, inevitably causing decreased breathing capacity and quality of life for patients. While animal models have paved the way for our understanding of pathobiology and the development of therapeutic strategies for disease management, their translational capacity is limited. There is, therefore, a well-recognised need for innovative in vitro models to reflect chronic lung diseases, which will facilitate mechanism investigation and the advancement of new treatment strategies. In the last decades, lungs have been modelled in healthy and diseased conditions using precision-cut lung slices, organoids, extracellular matrix-derived hydrogels and lung-on-chip systems. These three-dimensional models together provide a wide spectrum of applicability and mimicry of the lung microenvironment. While each system has its own limitations, their advantages over traditional two-dimensional culture systems, or even over animal models, increases the value of in vitro models. Generating new and advanced models with increased translational capacity will not only benefit our understanding of the pathobiology of lung diseases but should also shorten the timelines required for discovery and generation of new therapeutics. This article summarises and provides an outline of the European Respiratory Society research seminar "Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research", held in Lisbon, Portugal, in April 2022. Current in vitro models developed for recapitulating healthy and diseased lungs are outlined and discussed with respect to the challenges associated with them, efforts to develop best practices for model generation, characterisation and utilisation of models and state-of-the-art translational potential.

FIGURE 1

A general comparison of in vitro models used for modelling the lung: precision-cut lung slices, organoids, lung extracellular matrix (ECM)-derived hydrogels and lung-on-chip. The proportion of filled dots reflects the score of the model to fulfil the stated criterion, from least representative (one filled dot) to a complete lung in vitro (five filled dots). Lung ECM-derived hydrogel comparisons were based on cell-seeded hydrogels. Reported scores reflect the opinion of the authors and the meeting attendees rather than an objective scoring. E/M/V/I: epithelial cells/mesenchymal cells/vascular cells/immune cells.

FIGURE 2

Summary of the state-of-the-art status of different models used for modelling of different diseases. COPD: chronic obstructive pulmonary disease; ECM: extracellular matrix.