Journal
STEM CELL REPORTS
Volume 16, Issue 3, Pages 437-445Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2021.02.005
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Funding
- Career Award for Medical Scientists from the Burroughs Wellcome Fund USA
- National Institutes of Health USA [CA177322, DA039562, DA049524, AI125103, K08 AI130381]
- John and Mary Tu Foundation USA
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Researchers generated iPSC-derived lung and brain organoids, finding that lung organoids are highly permissive to SARS-CoV-2 infection, while brain organoids are less susceptible. These findings will aid in understanding the pathogenesis of COVID-19 and drug discovery.
COVID-19 is a transmissible respiratory disease caused by a novel coronavirus, SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons, and astrocytes. LORGs containing epithelial cells, alveolar types 1 and 2, highly express ACE2 and TMPRSS2 and are permissive to SARS-CoV-2 infection. SARS-CoV-2 infection induces interferons, cytokines, and chemokines and activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, and TMPRSS2 inhibitors (camostat/nafamostat) block viral entry in LORGs. Conversely, CORGs, NPCs, astrocytes, and neurons express low levels of ACE2 and TMPRSS2 and correspondingly are not highly permissive to SARS-CoV-2 infection. Infection in neuronal cells activates TLR3/7, OAS2, complement system, and apoptotic genes. These findings will aid in understanding COVID-19 pathogenesis and facilitate drug discovery.
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