Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction.
Abstract
Coronavirus infection causes diffuse alveolar damage leading to acute respiratory
distress syndrome. The absence of ex vivo models of human alveolar epithelium is hindering
an understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here, we report
a feeder-free, scalable, chemically defined, and modular alveolosphere culture system
for the propagation and differentiation of human alveolar type 2 cells/pneumocytes
derived from primary lung tissue. Cultured pneumocytes express the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) receptor angiotensin-converting enzyme receptor
type-2 (ACE2) and can be infected with virus. Transcriptome and histological analysis
of infected alveolospheres mirror features of COVID-19 lungs, including emergence
of interferon (IFN)-mediated inflammatory responses, loss of surfactant proteins,
and apoptosis. Treatment of alveolospheres with IFNs recapitulates features of virus
infection, including cell death. In contrast, alveolospheres pretreated with low-dose
IFNs show a reduction in viral replication, suggesting the prophylactic effectiveness
of IFNs against SARS-CoV-2. Human stem cell-based alveolospheres, thus, provide novel
insights into COVID-19 pathogenesis and can serve as a model for understanding human
respiratory diseases.
Type
Journal articleSubject
ACE2ARDS
SARS-CoV-2
cytokine storm
interferons
organoids
pneumocytes
protease
respiratory cells
surfactants
Permalink
https://hdl.handle.net/10161/21706Published Version (Please cite this version)
10.1016/j.stem.2020.10.005Publication Info
Katsura, Hiroaki; Sontake, Vishwaraj; Tata, Aleksandra; Kobayashi, Yoshihiko; Edwards,
Caitlin E; Heaton, Brook E; ... Tata, Purushothama Rao (2020). Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated
Interferon Responses and Pneumocyte Dysfunction. Cell stem cell. 10.1016/j.stem.2020.10.005. Retrieved from https://hdl.handle.net/10161/21706.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
Brook Heaton
Assistant Research Professor of Molecular Genetics and Microbiology
Nicholas Scott Heaton
Associate Professor of Molecular Genetics and Microbiology
Patty J Lee
Professor of Medicine
My overall research interests are in acute and chronic oxidant-induced lung injury
and repair, specifically the distinct roles of stress-response pathways depending
on the lung compartment or cell type(s) involved and their regulation by the immune
system. Using models of inhaled toxins, such as high oxygen concentrations, cigarette
smoke, and microbes, we discovered previously unrecognized mechanistic roles for innate
immune receptors, TLR4-NLRP3, mitochondrial health and cell fate, su
Aleksandra Tata
Assistant Research Professor of Cell Biology
Purushothama Rao Tata
Assistant Professor of Cell Biology
Lung regenerationLung stem cellsCell plasticityOrganoid modelsLung FibrosisSingle
Cell Biology
Alphabetical list of authors with Scholars@Duke profiles.

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info