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

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.

Broad-Spectrum Anti-coronavirus Vaccines and Therapeutics to Combat the Current COVID-19 Pandemic and Future Coronavirus Disease Outbreaks

“…Since hPSCs are able to differentiate into functional human cells, tissues, and organoids (Yang et al, 2020b), they are more reliable than the commonly used immortalized cell lines and more convenient and economic than animal models for drug discovery and evaluation. Several studies have shown that the organoids of blood vessel, intestine, kidney, brain, eye, lung, and liver can be infected by SARS-CoV-2 (Dickson, 2020; Makovoz et al, 2020;Ramani et al, 2020;Tindle et al, 2020;Yang et al, 2020b;Zhang et al, 2020a), and therefore they can be utilized for evaluation of nAbs and antiviral agents against SARS-CoV-2 infection. Monteil et al (2020) have demonstrated that clinical-grade soluble human ACE2, which has a similar action mechanism as some nAbs, can inhibit SARS-CoV-2 infection in hiPSCderived capillary organoids and hESC-derived kidney organoids.…”

Role of biomaterials in the diagnosis, prevention, treatment, and study of corona virus disease 2019 (COVID-19)

“…Pertinent tissue engineering work in combating the Coronavirus can be categorized as in vitro models to evaluate the proposed treatment efficiency, drug delivery approaches, and vaccines [18]. Among various tissue engineering techniques, 3D bioprinting [21][22][23], organoid engineering [24,25], and microfluidic organ-on-a-chip systems [26][27][28] are accepted to be the best approaches to design and develop effective in vitro tissue models [29].…”

“…The development of 3D organoids using bronchial transient epithelial cells that are usually attacked by SARS-CoV-2, can be useful to study and understand COVID-19 [34]. Tindle et al [25] created a complete adult stem cellderived lung organoid model . In vitro model was formed by adult lung organoids, primary airway cells, and humaninduced pluripotent stem cells (hiPSC)-derived alveolar type-II (AT2) pneumocytes.…”

“…Because animal models cannot fully recapitulate human physiology, in vitro microphysiological models such as organoids and organ-and lab-on-a-chip systems have been developed, with the ability to scale up and allow for a more accurate evaluation of drugs and vaccines [6,18]. To date, human organoid platforms including those of the small intestine [234,235], gut [236], kidney [79], and lung [25] for investigating SARS-CoV-2 were developed. For creating a reliable and biomimetic in vitro model, the multicellularity of organs such as the lung is a daunting challenge.…”

“…a Schematic showing the procedure for creating lung organoids (steps 1 and 2), supplemented with proximal and distal airway components in-a-dish model of COVID-19 (step 3) and cross-validation of in vitro lung models of SARS-CoV-2 infection (step 4). Adapted from [ 25 ]. b Confocal microscopy of immunohistochemistry, two months post-xenograft of hPSCs-derived pancreatic cells as in vitro model of COVID-19.…”