Researchers develop adult lung organoids that represent all cell types


Since the COVID-19 pandemic hit the United States in early 2020, scientists have struggled to find laboratory models of infection with SARS-CoV-2, the respiratory virus that causes COVID- 19. Animal models have failed; attempts to grow adult human lungs have historically failed because not all cell types have survived.

Steadfast, stem cell scientists, cell biologists, infectious disease experts and cardiothoracic surgeons from the University of California San Diego School of Medicine have teamed up to see if they can overcome several obstacles.

Written in a paper published on August 31, 2021, in eLife, the team describes the first adult human models of “lung in a box”, also known as lung organoids which represent all types of cells. They also report that SARS-CoV-2 infection of lung organoids mimics lung infections of real-world patients and reveals the specialized roles that various types of cells play in infected lungs.

“This model of human disease will now allow us to test the efficacy and toxicity of drugs and to reject ineffective compounds early in the process, in ‘phase 0’, before the start of clinical trials in humans,” he said. said Pradipta Ghosh, MD, professor, director of the Institute for Networked Medicine and executive director of the HUMANOID Center of Research Excellence (CoRE) at UC San Diego School of Medicine. Ghosh co-led the study with Soumita Das, PhD, associate professor of pathology at UC San Diego School of Medicine and founding co-director and scientific director of HUMANOID CoRE.

HUMANOID CoRE stem cell scientists, led by Das, reproducibly developed three lung organoid lines from adult stem cells derived from human lungs that had been surgically removed due to lung cancer. With a special cocktail of growth factors, they were able to maintain the cells that make up the upper and lower airways of the human lungs, including the specialized alveolar cells known as AT2.

By infecting lung organoids with SARS-CoV-2, the team found that cells in the upper respiratory tract are essential for the virus to establish infection, while cells in the lower respiratory tract are important for the immune response. . Both types of cells contribute to the overzealous immune response, sometimes referred to as a cytokine storm, which has been seen in severe cases of COVID-19.

A computer team led by Debashis Sahoo, Ph.D., assistant professor of pediatrics at UC San Diego School of Medicine and of Computer Science and Engineering at Jacobs School of Engineering, validated the novel lung organoids by comparing their gene expression patterns -; which genes are “on” or “off” -; to patterns reported in the lungs of patients who have succumbed to the disease, and to patterns they have previously discovered from databases of viral pandemic patients.

Whether or not they were infected with SARS-CoV-2, lung organoids behaved similarly to real-world lungs. In direct comparisons using the same endpoint (gene expression models), researchers have shown that their adult lung organoids replicate COVID-19 better than any other current laboratory model. Other models, for example, organoids derived from the fetal lung and models that rely solely on cells of the upper respiratory tract, allowed a robust viral infection but failed to elicit an immune response.

Our lung organoids are now ready to be used to explore the uncharted territory of COVID-19, including post-COVID complications, such as pulmonary fibrosis. We have already started testing drugs for their ability to control viral infection -; from entry to replication to propagation -; the runaway immune response that is so often fatal; and pulmonary fibrosis. “

Soumita Das, PhD, Associate Professor of Pathology, UC San Diego School of Medicine

Since their findings in human organoids are more likely to be relevant to human disease than findings in animal models or cell lines, the team hopes that successful drug candidates can move quickly to clinical trials.

“Because our HUMANOID Core lung organoids are scalable, customized, propagated and cost effective, they are unlike any other model in existence,” said Ghosh. “This is a significant breakthrough that may allow the modeling of lung diseases and pandemics beyond COVID-19. In fact, other academic and industrial partners are already starting to use these organoids in disease modeling and drug discovery. This is when I feel that research translation is immediately transformative.


Journal reference:

Tindle, C., et al. (2021) Complete lung organoid models derived from adult stem cells emulate lung disease in COVID-19. eLife.

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