TGen News

A unique spatial map of gene expression in 1.6 million cells from the lungs of people with pulmonary fibrosis (PF) and healthy controls revealed a surprising discovery: some lung tissue in these patients shows signs of the disease before significant structural remodeling of the tissue occurs.

The finding by a team of researchers co-led by TGen, part of City of Hope, could point to future therapeutic strategies that treat PF patients based on their individual stage of cellular and molecular remodeling.

If researchers could find ways of returning these molecularly dysregulated parts of the lung back to normal, “you would most likely improve patient lives and potentially outcomes for people because they’re going to start getting more oxygen when they get air into those spaces,” said Nicholas Banovich, Ph.D., an associate professor at TGen and co-senior author of the study.

The study results, published in Nature Genetics, also provide a conceptual roadmap of how cellular and molecular remodeling progresses during the disease, which could aid the development of treatments. Current treatments for the most common and severe form of PF only slow declining lung function, and most patients die or require lung transplantation within three to five years after their diagnosis.

Image-based spatial transcriptomics, the technique used by the scientists, is an important tool for studying PF, said Annika Vannan, Ph.D., a postdoctoral scholar in the Banovich lab and co-first author of the paper.

“The lung is spatially heterogeneous, there are a lot of different cell types that are present in different regions,” Vannan explained. “And each of the components along the respiratory tract are going to be affected differently by pulmonary fibrosis.”

To get a better view of this complexity, Vannan, Banovich and their colleagues profiled 343 genes in lung tissue samples from 26 people who underwent lung transplant for PF and from nine people without PF.

Their analysis helped them map out where cells with signs of PF occur, and identify the cellular and molecular underpinnings of some features of PF. Spatial transcriptomics has evolved so rapidly that the research team needed to develop new methods to analyze the data. “This work builds on a multi-year collaboration between my lab and the Banovich lab. We’re incredibly excited to be building best in class methods to better understand these data,” said Davis McCarthy, D.Phil., an associate professor and head of Bioinformatics and Cellular Genomics at the St. Vincent’s Institute in Melbourne, Australia, and a co-senior author of the study.

Using these newly built computational approaches, the team characterized12 distinct, molecularly defined spatial niches in healthy and PF-affected lungs.

“The diversity of disease progression among patients, combined with the complexities of large-scale data generated through super-resolution techniques present significant challenges in analysis. By implementing cutting-edge artificial intelligence tools, we were able to effectively detect abnormalities and uncover disease progression patterns within this comprehensive dataset,” said Ruqian Lyu, Ph.D., a postdoctoral fellow in the McCarthy lab and a co-first author of the study.

A surprising conclusion emerged: some regions of lung tissue that look normal still show clear signs of the disease.

“This study found that while there are noticeable changes at the molecular and cellular level, they haven’t yet caused the obvious structural damage seen in the more affected parts of the lung. We’re hopeful that by targeting these early changes, we might be able to prevent or even reverse the disease before patients experience significant lung function loss or severe symptoms from pulmonary fibrosis,” said Jonathan Kropski, M.D., an associate professor of medicine at Vanderbilt University Medical Center, and co-senior author of the study.

The study’s results support a model where the initial stages of the disease involve disruption of the cells lining the tiny air sacs in the lung called alveoli, followed by fibrotic remodeling and the proliferation of immune cells called macrophages in the late stages of the disease.

The size of the study’s dataset represents a major leap forward in the techniques and strategies used to conduct these types of analyses, the researchers said, noting that it took 35 research groups to contribute 2.4 million cells to the Human Cell Atlas Lung Project just two years ago

“The spatial transcriptomics technologies are new, and we have the privilege at TGen to be some of the first people using it at a pretty large scale,” Vannan said.

The TGen researchers will continue to expand their samples and look more closely at the mechanisms behind early PF in three research collaborations with their co-authors at Vanderbilt University Medical Center.

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The National Institutes of Health, Francis Family Foundation, Vanderbilt Faculty Research Scholars, the Department of Veterans Affairs, and the National Health and Medical Research Council funded this study.