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Accelerating drug development for lung diseases: New insights from single-cell genomics

Accelerating drug development for lung diseases: New insights from single-cell genomics
VWA1+/PLVAP+ ectopic ECs appear in alveolar septae of early-stage lung fibrosis. (a) Representative Immunofluorescence images of CLDN5 (green), PLVAP (red) and PDPN (white) expression in histopathological and microCT-staged IPF tissues. Yellow arrowheads indicate ectopic PLVAP+ vessels. White arrowheads mark PDPN+ lymphatics. Scale bars = 200 μm (overview images) and 50 μm (enlarged views). (b) Bar graphs show the quantification of PLVAP signal (percentage of PLVAP+ area to the total area of lung ROIs) in vivo (n = 5 control and n = 4 IPF patients). Statistics: Unpaired t-test. (c) Example images of quantification methodology of the alveolar PLVAP+ vessel area (normalized to the alveolar septal (AS) length) against the AS thickness. Representative alveolar septae of control and IPF1 tissues are shown. Scale bars = 50 μm. (d) The scatter plot shows the quantitative analysis of 60 AS derived from both control and IPF1 tissues, demonstrating a significant correlation of the normalized PLVAP+ vessel area with AS thickness (Pearson's r =0.69, P<0.0001, n = 5 control and n = 4 IPF1 patients). Credit: Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.adh0908

Drug development for lung diseases is complicated. Most clinical trials that test novel drugs fail due to the fact that laboratory models cannot accurately replicate human physiology.

Currently specific molecular pathways are often modeled in highly artificial conditions using one or two different cell types in a culture dish in the laboratory. Such simple systems do not fully replicate the tissue environment of the lung, and therefore these laboratory models are lacking representation of therapeutically relevant cell-cell communication pathways.

Revolutionizing pre-clinical drug development: Organotypic model system for lung research

A new promising experimental model to mechanistically study lung disease emerged recently: so-called human precision-cut lung slices (hPCLS). These are thin sections of lung tissue, that can be used for experiments in the lab.

To generate hPCLS, scientists from Helmholtz Munich work with human lung tissue obtained from patients undergoing surgery due to . The tissue gets cut into thin slices that can be kept alive in the lab. hPCLS have the unique advantage of retaining the full cellular diversity and native three-dimensional structure of the lung.

The team of researchers led by Prof. Schiller and Dr. Burgstaller have now performed an in-depth analysis of all cells within the hPCLS, thereby significantly advancing the possibilities and usage of this model.

They leveraged the power of single-cell genomics, which records gene activities in , to analyze the activity of all cells in hPCLS after specific experimental and therapeutic treatments.

Understanding treatment response: Insights from human precision-cut lung slices

The new advanced knowledge about hPCLS was used by the team to understand how disease-specific cellular activities that occur in lung fibrosis patients can be induced in the hPCLS model system, and how these disease specific cellular states can be affected by different anti-fibrotic drugs.

The authors computationally integrated several single-cell transcriptomic datasets from multiple patient cohorts and used (AI)-based transfer learning approaches to understand how cell states that were 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 comprehensive map detailing characteristics of all cell types within the human lung and was released earlier this year by Helmholtz Munich scientists and their international partners.

The new methods and insights from this study showcase the power of experimental studies in hPCLS to enable analysis of tissue homeostasis, regeneration and pathology.

Prof. Schiller says, "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." Ultimately, these efforts by Helmholtz Munich scientists have the capacity to significantly speed up the development of novel therapies.

The work is published in the journal Science Translational Medicine.

More information: Niklas J. Lang et al, Ex vivo tissue perturbations coupled to single-cell RNA-seq reveal multilineage cell circuit dynamics in human lung fibrogenesis, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.adh0908

Journal information: Science Translational Medicine
Citation: Accelerating drug development for lung diseases: New insights from single-cell genomics (2023, December 6) retrieved 21 February 2024 from
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