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Monitoring and manipulating cellular crosstalk during kidney fibrosis inside a 3D in vitro co-culture
Bramasta Nugraha1,2,3,4, Manuel A Mohr1, Aaron Ponti1
1Department of Biosystems Science and Engineering (D-BSSE), Eidgenössische Technische Hochschule (ETH) Zurich, Mattenstrasse 26, 4058, Basel, Switzerland.
Abstract:
In pharmacological research the development of promising lead compounds requires a detailed understanding of the dynamics of disease progression. However, for many diseases, such as kidney fibrosis, gaining such understanding requires complex real-time, multi-dimensional analysis of diseased and healthy tissue. To allow for such studies with increased throughput we established a dextran hydrogel-based in vitro 3D co-culture as a disease model for kidney fibrosis aimed at the discovery of compounds modulating the epithelial/mesenchymal crosstalk. This platform mimics a simplified pathological renal microenvironment at the interface between tubular epithelial cells and surrounding quiescent fibroblasts. We combined this 3D technology with epithelial reporter cell lines expressing fluorescent biomarkers in order to visualize pathophysiological cell state changes resulting from toxin-mediated chemical injury. Epithelial cell damage onset was robustly detected by image-based monitoring, and injured epithelial spheroids induced myofibroblast differentiation of co-cultured quiescent human fibroblasts. The presented 3D co-culture system therefore provides a unique model system for screening of novel therapeutic molecules capable to interfere and modulate the dialogue between epithelial and mesenchymal cells.
Insights
A novel 3D co-culture kidney fibrosis model using dextran hydrogels and fluorescent reporters enables real-time monitoring of epithelial cell damage and myofibroblast differentiation, aiding therapeutic compound discovery.
Area of Science:
- Pharmacology
- Biomedical Engineering
- Cell Biology
Background:
- Understanding kidney fibrosis progression is crucial for developing effective therapeutic compounds.
- Complex real-time, multi-dimensional analysis of diseased and healthy kidney tissue is often required.
- Existing models may lack the throughput or complexity to fully capture disease dynamics.
Purpose of the Study:
- To establish a high-throughput in vitro 3D co-culture model for kidney fibrosis.
- To mimic the renal microenvironment and study epithelial/mesenchymal crosstalk.
- To facilitate the discovery of compounds modulating this crosstalk.
Main Methods:
- Development of a dextran hydrogel-based 3D co-culture system.
- Incorporation of epithelial reporter cell lines with fluorescent biomarkers.
- Toxin-mediated chemical injury to induce disease progression.
- Image-based monitoring for detecting epithelial cell damage and myofibroblast differentiation.
Main Results:
- The 3D co-culture system successfully mimicked key aspects of kidney fibrosis pathology.
- Epithelial cell damage onset was robustly detected via image-based monitoring.
- Injured epithelial cells induced myofibroblast differentiation in co-cultured fibroblasts.
- The system demonstrated the epithelial/mesenchymal crosstalk central to fibrosis.
Conclusions:
- The developed 3D co-culture system serves as a unique and effective disease model for kidney fibrosis.
- This platform enables real-time visualization and analysis of pathophysiological changes.
- It is suitable for screening novel therapeutic molecules targeting epithelial-mesenchymal interactions in kidney fibrosis.
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