Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction

Cell Stem Cell. 2020 Dec 3;27(6):890-904.e8. doi: 10.1016/j.stem.2020.10.005. Epub 2020 Oct 21.


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.

Keywords: ACE2; ARDS; SARS-CoV-2; cytokine storm; interferons; organoids; pneumocytes; protease; respiratory cells; surfactants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Adult Stem Cells / drug effects
  • Adult Stem Cells / enzymology
  • Adult Stem Cells / virology*
  • Aged
  • Aged, 80 and over
  • Alveolar Epithelial Cells / drug effects*
  • Alveolar Epithelial Cells / enzymology
  • Alveolar Epithelial Cells / metabolism
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • COVID-19 / drug therapy*
  • COVID-19 / physiopathology
  • Cell Culture Techniques
  • Cell Differentiation
  • Female
  • Humans
  • Inflammation
  • Interferons / pharmacology*
  • Male
  • Mice
  • Receptors, Coronavirus / metabolism
  • SARS-CoV-2 / immunology*
  • Transcriptome
  • Virus Replication


  • Receptors, Coronavirus
  • Interferons
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2