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

• Published in: Cell reports (Cambridge) 2019-12, Vol.29 (11), p.3488-3505.e9
• Main Authors: Vijayaraj, Preethi, Minasyan, Aspram, Durra, Abdo, Karumbayaram, Saravanan, Mehrabi, Mehrsa, Aros, Cody J., Ahadome, Sarah D., Shia, David W., Chung, Katherine, Sandlin, Jenna M., Darmawan, Kelly F., Bhatt, Kush V., Manze, Chase C., Paul, Manash K., Wilkinson, Dan C., Yan, Weihong, Clark, Amander T., Rickabaugh, Tammy M., Wallace, W. Dean, Graeber, Thomas G., Damoiseaux, Robert, Gomperts, Brigitte N.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cells, Cultured; disease modeling; drug discovery; Drug Discovery - methods; Female; high content screening; Humans; induced pluripotent stem cells; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Male; Mice; Mice, Inbred C57BL; organ fibrosis; phenotypic drug screening; progressive fibrosis; Pulmonary Fibrosis - drug therapy; Small Molecule Libraries - pharmacology; Transforming Growth Factor beta - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.11.019

Progressive organ fibrosis accounts for one-third of all deaths worldwide, yet preclinical models that mimic the complex, progressive nature of the disease are lacking, and hence, there are no curative therapies. Progressive fibrosis across organs shares common cellular and molecular pathways involving chronic injury, inflammation, and aberrant repair resulting in deposition of extracellular matrix, organ remodeling, and ultimately organ failure. We describe the generation and characterization of an in vitro progressive fibrosis model that uses cell types derived from induced pluripotent stem cells. Our model produces endogenous activated transforming growth factor β (TGF-β) and contains activated fibroblastic aggregates that progressively increase in size and stiffness with activation of known fibrotic molecular and cellular changes. We used this model as a phenotypic drug discovery platform for modulators of fibrosis. We validated this platform by identifying a compound that promotes resolution of fibrosis in in vivo and ex vivo models of ocular and lung fibrosis. [Display omitted] •iPSC-derived cells provide a model for inflammation driven progressive fibrosis•A phenotypic drug screen using the model identified an anti-fibrotic molecule•The small molecule ameliorates fibrosis in animal and human disease models•The small molecule targets endogenous agonists of tissue repair Vijayaraj et al. describe the generation and characterization of an in vitro progressive fibrosis model that is broadly applicable to progressive organ fibrosis. They use it to identify a promising anti-fibrotic therapy that acts by activating normal tissue repair.