title: Development of a Three-Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling.
abstract: Stem cell technologies, especially patient-specific, induced stem cell pluripotency and directed differentiation, hold great promise for changing the landscape of medical therapies. Proper exploitation of these methods may lead to personalized organ transplants, but to regenerate organs, it is necessary to develop methods for assembling differentiated cells into functional, organ-level tissues. The generation of three-dimensional human tissue models also holds potential for medical advances in disease modeling, as full organ functionality may not be necessary to recapitulate disease pathophysiology. This is specifically true of lung diseases where animal models often do not recapitulate human disease. Here, we present a method for the generation of self-assembled human lung tissue and its potential for disease modeling and drug discovery for lung diseases characterized by progressive and irreversible scarring such as idiopathic pulmonary fibrosis (IPF). Tissue formation occurs because of the overlapping processes of cellular adhesion to multiple alveolar sac templates, bioreactor rotation, and cellular contraction. Addition of transforming growth factor-β1 to single cell-type mesenchymal organoids resulted in morphologic scarring typical of that seen in IPF but not in two-dimensional IPF fibroblast cultures. Furthermore, this lung organoid may be modified to contain multiple lung cell types assembled into the correct anatomical location, thereby allowing cell-cell contact and recapitulating the lung microenvironment. Our bottom-up approach for synthesizing patient-specific lung tissue in a scalable system allows for the development of relevant human lung disease models with the potential for high throughput drug screening to identify targeted therapies. Stem Cells Translational Medicine 2017;6:622-633.
authors.affiliation: Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Dan C
authors.initials: DC
authors.lastname: Wilkinson
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Department of Pediatrics, Children's Discovery and Innovation Institute, Los Angeles, California, USA.
authors.forename: Jackelyn A
authors.initials: JA
authors.lastname: Alva-Ornelas
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Department of Pediatrics, Children's Discovery and Innovation Institute, Los Angeles, California, USA.
authors.forename: Jennifer M S
authors.initials: JM
authors.lastname: Sucre
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Department of Pediatrics, Children's Discovery and Innovation Institute, Los Angeles, California, USA.
authors.forename: Preethi
authors.initials: P
authors.lastname: Vijayaraj
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Department of Pediatrics, Children's Discovery and Innovation Institute, Los Angeles, California, USA.
authors.forename: Abdo
authors.initials: A
authors.lastname: Durra
authors.affiliation: Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Wade
authors.initials: W
authors.lastname: Richardson
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Department of Pediatrics, Children's Discovery and Innovation Institute, Los Angeles, California, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Jonas
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Department of Pediatrics, Children's Discovery and Innovation Institute, Los Angeles, California, USA.
authors.forename: Manash K
authors.initials: MK
authors.lastname: Paul
authors.affiliation: Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Karumbayaram
authors.affiliation: Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Dunn
authors.affiliation: David Geffen School of Medicine at the University of California, Los Angeles, Department of Pediatrics, Children's Discovery and Innovation Institute, Los Angeles, California, USA.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Brigitte N
authors.initials: BN
authors.lastname: Gomperts
mesh_terms: D019149:Bioreactors; D018929:Cell Culture Techniques / Q000295:instrumentation; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000473:pathology* / Q000503:physiopathology; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000473:pathology*; D008168:Lung / Q000473:pathology* / Q000503:physiopathology; D009940:Organoids / Q000187:drug effects / Q000473:pathology*; D010641:Phenotype; D013997:Time Factors; D023822:Tissue Engineering / Q000295:instrumentation / Q000379:methods*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D053773:Transforming Growth Factor beta1
keywords: Disease modeling; Lung; Three-dimensional cell culture; Tissue engineering