Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule.

Area of Science:

• Biomedical Engineering
• Stem Cell Biology
• Pathology

Background:

• Progressive organ fibrosis is a major cause of mortality globally, with a lack of effective curative treatments.
• Existing preclinical models fail to capture the complex, progressive nature of fibrotic diseases.
• Shared cellular and molecular pathways underlie fibrosis across different organs, including chronic injury, inflammation, and aberrant repair.

Purpose of the Study:

• To develop and characterize a novel in vitro progressive organ fibrosis model.
• To utilize this model as a phenotypic drug discovery platform for anti-fibrotic agents.
• To identify and validate compounds that can promote fibrosis resolution.

Main Methods:

• Generation and characterization of an in vitro fibrosis model using induced pluripotent stem cell-derived cell types.
• The model recapitulates key fibrotic features: endogenous activated transforming growth factor β (TGF-β) production and progressive fibroblastic aggregate growth and stiffening.
• Phenotypic drug screening using the developed fibrosis model.

Main Results:

• The in vitro model successfully mimics progressive fibrosis with activated molecular and cellular changes.
• The model demonstrated its utility as a drug discovery platform.
• A novel compound was identified that effectively promotes fibrosis resolution in both in vivo and ex vivo ocular and lung fibrosis models.

Conclusions:

• A robust in vitro progressive fibrosis model was established using stem cell-derived cells.
• This model serves as an effective platform for phenotypic drug discovery in fibrosis.
• The identified compound shows therapeutic potential for treating fibrotic diseases.