Yale researchers create cellular model of chronic lung disease
Researchers at the Yale School of Medicine visualize cells affected by chronic obstructive pulmonary disease and anticipate future gene therapy treatments.
Ariane de Gennaro
A recent study led by researchers at the Yale School of Medicine has generated a way to visualize the cells in lungs affected by chronic obstructive pulmonary disease, or COPD.
COPD is typically caused by inhalation of pollutants such as cigarette smoke. Symptoms usually include coughing, difficulty breathing that gets progressively worse, inflammation and reduced lung function. The paper detailing the study’s findings was published in January in the Nature Communications journal and illustrates a cellular blueprint that allows researchers to measure the gene activity within each individual cell of a tissue sample, then compare the lungs of those with and without COPD. This research was led by assistant professor of medicine Maor Sauler, professor of medicine Naftali Kaminski, and John McDonough, an instructor at the Yale School of Medicine.
“COPD is … an important risk factor for respiratory infections (e.g. COVID-19) as well as other systemic diseases, like heart and vascular disease,” Sauler wrote in an email. “Yet, therapies for COPD are not very effective. Additionally, a disproportionate burden of COPD occurs in people of low economic status. As a pulmonologist, I see patients suffering with this disease and want to help.”
McDonough and Kaminski explained that some of the main challenges they faced when conducting the study were trying to coordinate it during the pandemic, analyzing large amounts of data generated by single-cell RNA sequencing and deriving conclusions from the raw data.
McDonough cited issues with trying to coordinate the project across multiple centers and obtaining reagents or tissue samples while working within the realm of public health restrictions as well as the challenge of extrapolating the data’s meaning to biology and extracting meaning from it.
“While data analysis is a huge challenge, what you do afterwards is also a challenge,” Kaminski wrote in an email. “Our teams at Yale PCCSM [Pulmonary, Critical Care, and Sleep Medicine] have incredible experience with such work, and a strong local and national network of collaborators and that helped.”
The researchers used single-cell RNA sequencing, a method that allowed them to measure the gene activity within each individual cell of a tissue sample to compare lung tissue from patients with and without COPD. Their analysis generated a cell blueprint that revealed the cellular and molecular changes characteristic of a lung with COPD.
The results suggested that genes known to be associated with predisposition to COPD were mostly expressed in structural cells of the lung and not infiltrating immune cells, a novel finding that highlights that the heritability of COPD is driven by structural rather than immune cells.
McDonough explained that COPD has been considered an inflammatory disease, which mainly infiltrates immune cells. But the study suggests that it could originate from structural cells and “the immune cells are just responding to this and doing what they are programmed to do.”
“COPD is considered an inflammatory disease — so this is surprising,” Kaminski wrote. “It highlights that the predisposition of COPD, or at least to very severe COPD, as we analyzed in this project, is driven by structural rather than immune cells. With additional studies this could lead to a paradigm shift in the disease.”
Sauler explained that the team plans to conduct further research to understand how specific genes identified in the study contribute to disease development while at the same time applying this technology to a more diverse group of individuals with COPD.
These findings have important implications for the future of COPD treatments, such as the further development of gene therapy procedures.
In 2019, COPD was the third leading cause of death worldwide, accounting for around 3.23 million deaths that year.