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

Tindle, Courtney; Fuller, MacKenzie; Fonseca, Ayden; Taheri, Sahar; Ibeawuchi, Stella-Rita; Beutler, Nathan; Katkar, Gajanan D.; Claire, Amanraj; Castillo, Vanessa; Hernandez, Moises; Russo, Hana; Duran, Jason; Crotty Alexander, Laura E.; Tipps, Ann; Lin, Grace; Thistlethwaite, Patricia A.; Chattopadhyay, Ranajoy; Rogers, Thomas F.; Sahoo, Debashis; Ghosh, Pradipta; Das, Soumita

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 HIGHLIGHTS Human lung organoids with mixed proximodistal epithelia are created Proximal airway cells are critical for viral infectivity Distal alveolar cells are important for emulating host response Both are required for the overzealous response in severe COVID-19 IN BRIEF An 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.