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

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

Cell Reports (Dec 2019)

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

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

Affiliations

Preethi Vijayaraj: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA
Aspram Minasyan: Department of Molecular & Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
Abdo Durra: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Saravanan Karumbayaram: Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA
Mehrsa Mehrabi: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Cody J. Aros: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Sarah D. Ahadome: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
David W. Shia: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Katherine Chung: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Jenna M. Sandlin: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Kelly F. Darmawan: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Kush V. Bhatt: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Chase C. Manze: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Manash K. Paul: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Dan C. Wilkinson: Department of Materials Science and Engineering, UCLA, Los Angeles, CA 90095, USA
Weihong Yan: Department of Biology and Biochemistry, UCLA, Los Angeles, CA 90095, USA
Amander T. Clark: Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA; Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA
Tammy M. Rickabaugh: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
W. Dean Wallace: Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA 90095, USA
Thomas G. Graeber: Department of Molecular & Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA
Robert Damoiseaux: Department of Molecular & Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA
Brigitte N. Gomperts: UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA; UCLA Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Corresponding author

Journal volume & issue: Vol. 29, no. 11
pp. 3488 – 3505.e9

Abstract

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Summary: 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. : 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. Keywords: disease modeling, induced pluripotent stem cells, progressive fibrosis, drug discovery, phenotypic drug screening, organ fibrosis, high content screening

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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