Stem cell organoids to reveal new treatments for COVID-19

Mini lungs grown from stem cells have helped to better understand the mechanism of lung damage in COVID-19. The researchers were able to detail the mechanisms behind SARS-CoV-2 infection and early innate immune response in the lungs.

To date, there have been more than 40 million COVID-19 cases and nearly 1.13 million deaths worldwide. The main target tissues of SARS-CoV-2, the virus that causes COVID-19, especially in patients with pneumonia, appear to be alveoli – tiny spherical structures in the lungs where oxygen passes into the blood and removes carbon dioxide from blood.

To better understand how SARS-CoV-2 infects the lungs and causes disease, a team of scientists from the UK and South Korea turned to organoids – “mini-organs” grown in three dimensions to mimic the behavior of tissues and organs.

The team used tissue donated to a tissue bank at Royal Papworth Hospital to obtain specialized cells known as human lung alveolar type 2 cells. Then the development of these cells was reversed, reprogramming these cells back to their earlier ‘stem cell’ stage from which self-organizing alveolar-like three-dimensional structures were grown that mimic the basic tissue of the lung.

Dr Joo-Hyeon Lee, co-senior author of an article published in Cell Stem Cell, and a Group Leader at the Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, said: “We still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease. Our approach has allowed us to grow 3D models of key lung tissue – in a sense, ‘mini-lungs’ – in the lab and study what happens when they become infected”.

The team infected the organoids with the SARS-CoV-2 strain from a South Korean patient who was diagnosed with COVID-19 after traveling to Wuhan, China, in January. Using a combination of fluorescence imaging and single cell DNA sequencing, the scientists were able to study the cells response to the virus.

When three-dimensional models were exposed to SARS-CoV-2, the virus began to replicate rapidly, infecting all cells just six hours after infection. Replication allows the virus to spread throughout the body, infecting other cells and tissues.

Around the same time, cells began to produce interferons – proteins that act as warning signals to neighboring cells, activating their antiviral defenses. After 48 hours, interferons triggered an innate immune response, the first line of defense, and the cells began to resist infection.

Sixty hours after infection, some of the alveolar cells began to disintegrate, which led to cell death and damage to the lung tissue.

Although the researchers observed changes in lung cells within three days of infection, clinical symptoms of COVID-19 rarely develop as quickly and can sometimes appear more than 10 days after infection.

The team believes there are several possible reasons for this. It can take several days from the first penetration of the virus into the upper respiratory tract to its entry into the alveoli. It may also be necessary to infect a certain number of alveolar cells to initiate further interaction with the immune system, leading to inflammation, before the patient develops the first symptoms.

“Based on our model we can tackle many unanswered key questions, such as understanding genetic susceptibility to SARS-CoV-2, assessing relative infectivity of viral mutants, and revealing the damage processes of the virus in human alveolar cells”, – said Dr Young Seok Ju, co-senior author, and an Associate Professor at Korea Advanced Institute of Science and Technology. “Most importantly, it provides the opportunity to develop and screen potential therapeutic agents against SARS-CoV-2 infection.”

“We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue”, – added Dr Lee.