Lung disease medication development: Single-cell genomics insights

It is difficult to create drugs for lung disease. Most clinical trials for new medications fail because laboratory models cannot adequately imitate human physiology.

Currently, individual biochemical pathways are frequently recreated in very artificial settings in the laboratory utilizing one or two different cell types in a culture dish. These laboratory models lack representation of therapeutically critical cell-cell communication pathways because such simple systems do not fully recreate the tissue environment of the lung.

Organotypic model system for lung research is revolutionizing pre-clinical drug development

Human precision-cut lung slices (hPCLS) are a potentially promising experimental paradigm for studying lung disease mechanistically. These are thin pieces of lung tissue that can be employed in laboratory research.

Helmholtz Munich scientists create hPCLS using human lung tissue acquired from patients undergoing lung disease surgery. The tissue is split into small slices so that it can be preserved in the lab. hPCLS have the distinct advantage of preserving the lung’s full cellular diversity and original three-dimensional structure.

Prof. Schiller and Dr. Burgstaller’s team of researchers have now completed an in-depth investigation of all cells within the hPCLS, considerably extending the potential and application of this lung disease model.

They used single-cell genomics, which records gene activities in individual cells, to examine the activity of all cells in hPCLS after various experimental and therapeutic treatments.

Insights from human precision-cut lung slices into therapy response

The scientists used their new expanded knowledge of hPCLS to understand how disease-specific cellular activities that occur in lung fibrosis patients can be produced in the hPCLS model system, and how different anti-fibrotic medicines alter these disease-specific cellular states.

The authors used artificial intelligence (AI)-based transfer learning approaches to understand how cell states induced by cytokine and drug treatments in the hPCLS model compare to the Human Lung Cell Atlas (HLCA) of health and disease.

The HLCA is a detailed map of all cell types in the human lung that was revealed earlier this year by Helmholtz Munich scientists and worldwide collaborators.

This study’s new approaches and findings demonstrate the power of experimental investigations in hPCLS for analyzing tissue homeostasis, regeneration, and pathology.

Prof. Schiller goes on to explain, “We are now working on doing these hPCLS perturbation experiments at scale to learn more about the regulation of lung tissue states in health and disease and provide an experimental model for drug testing directly in human lung tissue.” Finally, the activities of Helmholtz Munich experts have the potential to dramatically accelerate the creation of new medicines.

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