1. Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction.
- Author
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Katsura H, Sontake V, Tata A, Kobayashi Y, Edwards CE, Heaton BE, Konkimalla A, Asakura T, Mikami Y, Fritch EJ, Lee PJ, Heaton NS, Boucher RC, Randell SH, Baric RS, and Tata PR
- Subjects
- Adult, Adult Stem Cells drug effects, Adult Stem Cells enzymology, Aged, Aged, 80 and over, Alveolar Epithelial Cells enzymology, Alveolar Epithelial Cells metabolism, Angiotensin-Converting Enzyme 2 metabolism, Animals, COVID-19 physiopathology, Cell Culture Techniques, Cell Differentiation, Female, Humans, Inflammation, Male, Mice, Receptors, Coronavirus metabolism, Transcriptome, Virus Replication, Adult Stem Cells virology, Alveolar Epithelial Cells drug effects, Interferons pharmacology, SARS-CoV-2 immunology, COVID-19 Drug Treatment
- 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., Competing Interests: Declaration of Interests A patent application (PCT/US20/53158) related to this work has been filed. H.K. and P.R.T. are listed as co-inventors on this application. P.R.T. serves as a consultant for Cellarity and Surrozen., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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