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

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

Cell reports (2019-12-12)
Preethi Vijayaraj, Aspram Minasyan, Abdo Durra, Saravanan Karumbayaram, Mehrsa Mehrabi, Cody J Aros, Sarah D Ahadome, David W Shia, Katherine Chung, Jenna M Sandlin, Kelly F Darmawan, Kush V Bhatt, Chase C Manze, Manash K Paul, Dan C Wilkinson, Weihong Yan, Amander T Clark, Tammy M Rickabaugh, W Dean Wallace, Thomas G Graeber, Robert Damoiseaux, Brigitte N Gomperts
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium hydrogen sulfate, technical grade
Sigma-Aldrich
p-Benzoquinone, reagent grade, ≥98%
Sigma-Aldrich
1,4-Dioxane, anhydrous, 99.8%, contains <=25 ppm BHT as stabilizer
Sigma-Aldrich
Albumin from chicken egg white, lyophilized powder, ≥98% (agarose gel electrophoresis)
Millipore
MILLIPLEX® TGFß Magnetic Bead 3 Plex Kit - Immunology Multiplex Assay, for quantification of TGFß1, TGFß2 and TGFß3 in multiple species
Sigma-Aldrich
LX-2 Human Hepatic Stellate Cell Line, a highly suitable model of human hepatic fibrosis