Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), causes large-scale damage to the lungs triggered by a massive immune response. It causes inflammation and injury in the lungs and gives rise to diffuse alveolar damage resulting in the apoptosis of alveolar pneumocytes and pulmonary edema. The origins of this overzealous immune response are still unknown.
Although some preclinical animal models developed earlier by scientists have emulated some aspects of infection such as induction and transmission of disease, most of these models did not develop severe clinical symptoms. The human lung's multicellularity has always been a challenge for scientists to recreate in vitro, especially in the current context of the COVID-19 pandemic.
Recently, a team of researchers from the University of California San Diego and The Scripps Research Institute, CA, USA, showed that an integrated stem cell-based disease modeling and computational approach is crucial for simulating the host immune response in fatal COVID-19 patients. Their work is published on the preprint server, bioRxiv* in October 2020.
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.
New adult lung organoid model has both proximal airway and distal alveolar cell types
In this study, the researchers present a transdisciplinary approach to systematically assess an adult lung organoid model that is complete with proximal airway and distal alveolar cell types and also can be personalized. The researchers aim to provide a scalable and affordable adult stem cell-based human lung organoid model with both a mixture of epithelial cells.
The team cross-validated all types of lung cells against respiratory samples taken from COVID-19 patients. The results showed that cellular crosstalk between proximal and distal components is critical to show how SARS-CoV-2 causes diffuse alveolar pneumocyte damage. Although the proximal airway triggers a sustained viral infection, it is the distal alveolar pneumocytes that cause the massive host immune response seen in fatal disease.
Adult lung organoid cells recapitulated transcriptomic signatures better than other cells
In the study, monolayers were derived from primary airway cells, adult lung organoids, or hiPSC-derived alveolar type-II pneumocytes. They were infected with SARS-CoV-2 to produce in vitro lung models of COVID-19. Infected adult lung organoid monolayers recapitulated the transcriptomic signatures better than the others in respiratory samples derived from diverse cohorts of COVID-19 patients. The airway (proximal) cells played a key role in sustained viral infection, whereas distal alveolar differentiation
(AT2 → AT1) was critical for intensifying the immune response of the host in fatal COVID-19.
"We have provided the evidence that the organoids that were created using our methodology retain proximal and distal cellularity throughout multiple passages and even within the same organoid."
New human lung model can help in the study of COVID-19 pathogenesis
The findings of the study validate a human lung model of COVID-19 that can be utilized to study. COVID-19 pathogenesis and develop new therapies and vaccines to fight the pandemic. According to the team, their study's most significant discovery is the adult lung organoids created with both proximal airway and distal alveolar epithelia. These organoids can be easily propagated in 3D cultures and can also be used as mixed-cell monolayers for modeling viral and host immune responses in viral pandemics that cause respiratory distress. Moreover, a comparison of this model with existing
SARS-CoV-2-infected lung models showed that this model best emulates lung injury, viral infectivity, and inflammation in COVID-19 patients.
The three important impacts of this study as per the team are: (1) first-time successful modeling of the human lung organoids complete with both proximal and distal signatures; (2) the new lung model has four fundamental properties – reproducibility and scalability, cost-effectiveness, personalization, and modularity - that other existing lung models lack; and (3) enhanced value of adult lung organoid models thanks to the availability of companion readouts and biomarkers that can vet treatment efficacy rapidly based on pre-set therapeutic goals.
"The most important discovery we report here is the creation of adult lung organoids that are complete with both proximal airway and distal alveolar epithelia; these organoids can not only be stably propagated and expanded in 3D cultures but also used as monolayers of mixed cellularity for modeling viral and host immune responses during respiratory viral pandemics."
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19 Courtney Tindle, MacKenzie Fuller, Ayden Fonseca, Sahar Taheri, Stella-Rita Ibeawuchi, Nathan Beutler, Amanraj Claire, Vanessa Castillo, Moises Hernandez, Hana Russo, Jason Duran, Laura E. Crotty Alexander, Ann Tipps, Grace Lin, Patricia A. Thistlethwaite, Ranajoy Chattopadhyay, Thomas F. Rogers, Debashis Sahoo, Pradipta Ghosh, Soumita Das bioRxiv 2020.10.17.344002; doi: https://doi.org/10.1101/2020.10.17.344002, https://www.biorxiv.org/content/10.1101/2020.10.17.344002v2