Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19

Tindle, C.; Fuller, M.; Fonseca, A.; Taheri, S.; Ibeawuchi, S.-R.; Beutler, N.; Claire, A.; Castillo, V.; Hernandez, M.; Russo, H.; Duran, J.; Crotty Alexander, L. E.; Tipps, A.; Lin, G.; Thistlethwaite, P. A.; Chattopadhyay, R.; Rogers, T. F.; Sahoo, D.; Ghosh, P.; Das, S.

doi:10.1101/2020.10.17.344002

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bioRxiv · 10.1101/2020.10.17.344002

Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19

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Abstract

SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type-II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. Infected ALO-monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2[->]AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/344002v4_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1d1507aorg.highwire.dtl.DTLVardef@faa17forg.highwire.dtl.DTLVardef@80ceb1org.highwire.dtl.DTLVardef@81d61c_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIHuman lung organoids with mixed proximodistal epithelia are created C_LIO_LIProximal airway cells are critical for viral infectivity C_LIO_LIDistal alveolar cells are important for emulating host response C_LIO_LIBoth are required for the overzealous response in severe COVID-19 C_LI IN BRIEFAn integrated stem cell-based disease modeling and computational approach demonstrate how both proximal airway epithelium is critical for SARS-CoV-2 infectivity, but distal differentiation of alveolar pneumocytes is critical for simulating the overzealous host response in fatal COVID-19.

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Tindle, C., Fuller, M., Fonseca, A., Taheri, S., Ibeawuchi, S.-R., Beutler, N., Claire, A., Castillo, V., Hernandez, M., Russo, H., Duran, J., Crotty Alexander, L. E., Tipps, A., Lin, G., Thistlethwaite, P. A., Chattopadhyay, R., Rogers, T. F., Sahoo, D., Ghosh, P., Das, S.. 2020-10-18. Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19. https://doi.org/10.1101/2020.10.17.344002

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