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      Efficient Generation and Transcriptomic Profiling of Human iPSC-Derived Pulmonary Neuroendocrine Cells

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          Summary

          Expansion of pulmonary neuroendocrine cells (PNECs) is a pathological feature of many human lung diseases. Human PNECs are inherently difficult to study due to their rarity (<1% of total lung cells) and a lack of established protocols for their isolation. We used induced pluripotent stem cells (iPSCs) to generate induced PNECs (iPNECs), which express core PNEC markers, including ROBO receptors, and secrete major neuropeptides, recapitulating known functions of primary PNECs. Furthermore, we demonstrate that differentiation efficiency is increased in the presence of an air-liquid interface and inhibition of Notch signaling. Single-cell RNA sequencing (scRNA-seq) revealed a PNEC-associated gene expression profile that is concordant between iPNECs and human fetal PNECs. In addition, pseudotime analysis of scRNA-seq results suggests a basal cell origin of human iPNECs. In conclusion, our model has the potential to provide an unlimited source of human iPNECs to explore PNEC pathophysiology associated with several lung diseases.

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          Highlights

          • PNECs can be efficiently generated from induced pluripotent stem cells (iPSCs)

          • Induced PNECs express key PNEC markers and express and secrete all major neuropeptides

          • Induced PNECs resemble the transcriptomic profile of human primary fetal PNECs

          • Basal cells are able to differentiate into PNECs

          Abstract

          Cell Biology; Stem Cells Research; Transcriptomics

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          Most cited references 44

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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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              Neuronal morphometry directly from bitmap images.

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                Author and article information

                Contributors
                Journal
                iScience
                iScience
                iScience
                Elsevier
                2589-0042
                21 April 2020
                22 May 2020
                21 April 2020
                : 23
                : 5
                Affiliations
                [1 ]Hastings Center for Pulmonary Research and Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
                [2 ]Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, HMR 712, University of Southern California, Los Angeles, CA 90033, USA
                [3 ]Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
                [4 ]Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
                [5 ]Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63105, USA
                [6 ]Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
                [7 ]Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
                [8 ]Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109, USA
                [9 ]Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
                [10 ]Norris Comprehensive Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
                [11 ]Division of Hematology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
                Author notes
                []Corresponding author ichida@ 123456usc.edu
                [∗∗ ]Corresponding author amy.firth@ 123456med.usc.edu
                [∗∗∗ ]Corresponding author zborok@ 123456med.usc.edu
                [12]

                Lead Contact

                Article
                S2589-0042(20)30268-6 101083
                10.1016/j.isci.2020.101083
                7205764
                32380423
                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Article

                cell biology, stem cells research, transcriptomics

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