3-D cell cultures that resemble lung buds. In the real embryo, the green cells would form airways, while the red cells would become alveoli. Photo credit: Rockefeller University

When SARS-CoV-2 began its rapid spread around the world, it took scientists only a few months to develop the first tools to study or neutralize the virus. What has so far been missing, however, are reliable methods of localizing the disease – not the pathogen itself, but the complex biological events that take place in infected human cells and tissues.

Studies aimed at understanding how COVID-19 ravages the lungs, for example, has often been done on a variety of lung cancer cells that differ significantly from those affected by the virus.

“There were too many shifts for precise work,” says Ali H. Brivanlou, Robert and Harriet Heilbrunn professor at Rockefeller.

Now Brivanlou’s laboratory is introducing stem cell-based technology that enables mass-produced tissue cultures that mimic lung buds, the embryonic structures that form our respiratory organs. When these synthetic “micro-lungs” are infected with SARS-CoV-2 in the laboratory, they offer a powerful model to study the mechanisms of COVID-19 and to search for new drugs.

The results are available online on the bioRxiv preprint server before they are published in a peer-reviewed journal.

From carpets to lumps

Postdoctoral fellow Edwin Rosado Olivieri arrived at Brivanlou’s laboratory in early 2020, just before New York State was locked down. As a former PhD student at Harvard University, he had come to study how visceral organs such as the intestines, liver and pancreas take shape during embryonic development, but immediately switched plans to work on the novel coronavirus.

In common laboratory experiments, cells are grown in a single-layer carpet, clinging firmly to the bottom of the dish without receiving much input from their neighbors. To see if he could get laboratory-made stem cells to organize themselves into something more similar to embryonic lung tissue, Rosado Olivieri instead grew them in an elaborate matrix and made the cells climb over each other and exchange messages, like real stem cells do this in the course of development.

At carefully set times, he stimulated the cells with signals that mimick those that control the differentiation of lung cells in embryonic networks. By two weeks, the cells had formed identical buds whose molecular profiles closely matched those in the earliest stages of fetal lung development – including the formation of airways and alveoli, structures known to be found in many people with severe COVID-19 are damaged.

Mimicking the disease

Next, the researchers bathed the lung buds with three COVID-19 antibodies, two of which are being studied in human studies, and worked with colleagues in Charles M. Rice’s laboratory to infect the buds with SARS-CoV-2. These experiments showed that the infected buds provide a realistic model of disease that can be used to assess the effectiveness of novel drug compounds. As the scientists had hoped, various combinations of antibodies inhibited the infection at levels similar to those seen in previous experiments.

The researchers say other efforts have been made to study COVID-19 in synthetic tissues such as lung organoids, but emphasize that the new system is uniquely practical in that it can easily be scaled up to produce large amounts of lung tissue. “With the synthetic human lung buds, we can summarize important features of the disease that are otherwise inaccessible for experiments,” says Rosado Olivieri. “They give us the opportunity to understand how this virus interacts with lung cells and induces pathologies.”

In addition, by providing an unlimited source of disease-related tissue, the model will enable large chemical libraries to be screened for drugs that could potentially be used to “block and fight COVID-19 or other respiratory viruses that may appear in the future”. “Rosado Olivieri says. And its uses could go further.

“The lung buds will allow us to summarize the molecular events that drive normal lung development, as well as the underlying lung cancers, respiratory infections and a range of lung diseases for which there are currently no treatments,” says Brivanlou.

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More information:
EA Rosado-Olivieri et al. Self-organized human lung buds from stem cells with proximo-distal structuring and new targets of SARS-CoV-2, bioRxiv (2021). DOI: 10.1101 / 01.06.2021.425622 Provided by Rockefeller University

Quote: Synthetic microlungs could take COVID-19 research to the next level (2021, January 21), which will be released on January 21, 2021 at https://medicalxpress.com/news/2021-01-synthetic-micro-lungs- covid-.html was obtained

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