The US researchers have grown mini human lungs in labdishes using adult stem cells, featuring all types of cells that make up thehuman organ, allowing for testing of new treatments for respiratory diseases,including Covid-19.
Attempts to grow adult human lungs have historicallyfailed because not all of the cell types survived.
The first adult human "lung-in-a-dish" models,described in the journal eLife, are also known as lung organoids and representall cell types.
The SARS-CoV-2 infection of the lung organoids replicatesreal-world patient lung infections, and reveals the specialised roles variouscell types play in infected lungs, said the team at the University ofCalifornia-San Diego.
"This human disease model will now allow us to testdrug efficacy and toxicity, and reject ineffective compounds early in theprocess, at 'Phase 0', before human clinical trials begin," said PradiptaGhosh, Professor, at UC San Diego School of Medicine.
The stem cell scientists reproducibly developed three lungorganoid lines from adult stem cells derived from human lungs that had beensurgically removed due to lung cancer. With a special cocktail of growthfactors, they were able to maintain cells that make up both the upper and lowerairways of human lungs, including specialized alveolar cells known as AT2.
By infecting the lung organoids with SARS-CoV-2, the teamdiscovered that the upper airway cells are critical for the virus to establishinfection, while the lower airway cells are important for the immune response.Both cell types contribute to the overzealous immune response, sometimes calleda cytokine storm that has been observed in severe cases of Covid-19.
A computational team validated the new lung organoids bycomparing their gene expression patterns -- which genes are "on" or"off" -- to patterns reported in the lungs of patients who succumbedto the disease, and to those that they previously uncovered from databases ofviral pandemic patient data.
Whether infected or not with SARS-CoV-2, the lungorganoids behaved similar to real-world lungs. In head-to-head comparisonsusing the same yardstick (gene expression patterns), the researchers showedthat their adult lung organoids replicated Covid-19 better than any othercurrent lab model.
Other models, for example foetal lung-derived organoidsand models that rely only on upper airway cells, allowed robust viralinfection, but failed to mount an immune response.
"Our lung organoids are now ready to use to explorethe uncharted territory of Covid-19, including post-Covid complications, suchas lung fibrosis," said Soumita Das, PhD, associate professor of pathologyat UC San Diego.
"We have already begun to test drugs for theirability to control viral infection -- from entry to replication to spread --the runaway immune response that is so often fatal, and lung fibrosis,"she added.