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Progenitor identification and SARS-CoV-2 infection in human distal lung organoids
Progenitor identification and SARS-CoV-2 infection in human distal lung organoids
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Progenitor identification and SARS-CoV-2 infection in human distal lung organoids
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Progenitor identification and SARS-CoV-2 infection in human distal lung organoids
Progenitor identification and SARS-CoV-2 infection in human distal lung organoids

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Progenitor identification and SARS-CoV-2 infection in human distal lung organoids
Progenitor identification and SARS-CoV-2 infection in human distal lung organoids
Journal Article

Progenitor identification and SARS-CoV-2 infection in human distal lung organoids

2020
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Overview
The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5 + basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5 + cells in basal organoids revealed a distinct population of ITGA6 + ITGB4 + mitotic cells, whose offspring further segregated into a TNFRSF12A hi subfraction that comprised about ten per cent of KRT5 + basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia. A long-term culture method for organoids derived from single adult human lung cells is used to identify progenitor cells and study SARS-CoV-2 infection.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject

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/ 13/106

/ 14

/ 14/1

/ 14/19

/ 14/32

/ 38

/ 38/91

/ 45

/ 631/326/596/1578

/ 631/326/596/4130

/ 631/532/2118

/ 82

/ ACE2

/ Alveolar Epithelial Cells - cytology

/ Alveolar Epithelial Cells - metabolism

/ Alveolar Epithelial Cells - virology

/ Alveoli

/ Angiotensin-converting enzyme 2

/ Basal cells

/ Bronchopulmonary infection

/ Cell culture

/ Cell cycle

/ Cell Differentiation

/ Cell Division

/ Clone Cells - cytology

/ Clone Cells - metabolism

/ Clone Cells - virology

/ Coronaviridae

/ Coronaviruses

/ COVID-19

/ COVID-19 - metabolism

/ COVID-19 - pathology

/ COVID-19 - virology

/ Culture

/ Disease transmission

/ Gas exchange

/ Genes

/ Heterogeneity

/ Human cell culture

/ Humanities and Social Sciences

/ Humans

/ In Vitro Techniques

/ Infections

/ Influenza A Virus, H1N1 Subtype - growth & development

/ Influenza A Virus, H1N1 Subtype - physiology

/ Integrin alpha6 - analysis

/ Integrin beta4 - analysis

/ Keratin-5 - analysis

/ Lumens

/ Lung - cytology

/ Lung cancer

/ Lung diseases

/ Lungs

/ Methods

/ Models, Biological

/ multidisciplinary

/ Offspring

/ Organoids

/ Organoids - cytology

/ Organoids - metabolism

/ Organoids - virology

/ Physiological aspects

/ Pneumonia

/ Pneumonia, Viral - metabolism

/ Pneumonia, Viral - pathology

/ Pneumonia, Viral - virology

/ Polarity

/ Respiratory diseases

/ SARS-CoV-2 - growth & development

/ SARS-CoV-2 - physiology

/ Science

/ Science (multidisciplinary)

/ Severe acute respiratory syndrome coronavirus 2

/ Single-Cell Analysis

/ Stem cells

/ Tissue Culture Techniques

/ TWEAK Receptor - analysis

/ Viral diseases