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      A three-dimensional model of human lung development and disease from pluripotent stem cells

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          Abstract

          Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative strategies for disease modeling, drug discovery and regenerative medicine 1 . We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants 2 , led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs 3 . Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis 4, 5 , led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease.

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          Most cited references34

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          Preparing for the first breath: genetic and cellular mechanisms in lung development.

          The mammalian respiratory system--the trachea and the lungs--arises from the anterior foregut through a sequence of morphogenetic events involving reciprocal endodermal-mesodermal interactions. The lung itself consists of two highly branched, tree-like systems--the airways and the vasculature--that develop in a coordinated way from the primary bud stage to the generation of millions of alveolar gas exchange units. We are beginning to understand some of the molecular and cellular mechanisms that underlie critical processes such as branching morphogenesis, vascular development, and the differentiation of multipotent progenitor populations. Nevertheless, many gaps remain in our knowledge, the filling of which is essential for understanding respiratory disorders, congenital defects in human neonates, and how the disruption of morphogenetic programs early in lung development can lead to deficiencies that persist throughout life. (c) 2010 Elsevier Inc. All rights reserved.
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            Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency.

            Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity. Copyright © 2015, American Association for the Advancement of Science.
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              Highly efficient generation of airway and lung epithelial cells from human pluripotent stem cells

              The ability to generate lung and airway epithelial cells from human pluripotent stem cells (hPSCs) would have applications in regenerative medicine, drug screening and modeling of lung disease, and studies of human lung development. We established, based on developmental paradigms, a highly efficient method for directed differentiation of hPSCs into lung and airway epithelial cells. Long-term differentiation in vivo and in vitro yielded basal, goblet, Clara, ciliated, type I and type II alveolar epithelial cells. Type II alveolar epithelial cells generated were capable of surfactant protein-B uptake and stimulated surfactant release, providing evidence of specific function. Inhibiting or removing agonists to signaling pathways critical for early lung development in the mouse—retinoic acid, Wnt and BMP—recapitulated defects in corresponding genetic mouse knockouts. The capability of this protocol to generate most cell types of the respiratory system suggests its utility for deriving patient-specific therapeutic cells.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                21 December 2017
                24 April 2017
                May 2017
                22 January 2018
                : 19
                : 5
                : 542-549
                Affiliations
                [1 ]Columbia Center for Human Development, Columbia University Medical Center, New York, NY 10032, USA
                [2 ]Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA
                [3 ]Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
                [4 ]Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal
                [5 ]ICVS/3B's, PT Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal
                [6 ]Division of Immunology and Manton Center for Orphan Disease Research, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
                [7 ]U.O. Pediatria 2, Istituto Giannina Gaslini, Genoa, Italy
                [8 ]St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
                [9 ]OCS Microscopy Core, New York University Langone Medical Center, New York, NY 10016
                [10 ]Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA
                [11 ]Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA
                [12 ]Department of Physiology & Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
                [13 ]Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, NY 10032, USA
                Author notes
                [14 ]Correspondence should be addressed to H.W.S hs2680@ 123456columbia.edu
                Article
                NIHMS860304
                10.1038/ncb3510
                5777163
                28436965
                5d3e6d9a-9de6-4ecf-8cb5-f3da66700a2b

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                Cell biology
                Cell biology

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