Study uses spatial transcriptomics to link molecular profiles with tissue architecture in normal and injured lungs
PHOENIX, Ariz. (August 13, 2025) — A research team led by investigators at the Translational Genomics Research Institute (TGen), part of City of Hope, have created a high-resolution spatial atlas of the developing human lung, mapping how cells grow, interact, and organize themselves to ensure proper gas exchange within the lung — and how premature birth and injury disrupt that process.
The scientists used image-based spatial transcriptomics to examine ~1.2 million cells from 17 human infant lungs across a range of gestational ages, postnatal life spans, and disease states. By localizing cellular and molecular profiles within each tissue sample, the atlas shows how lung development unfolds in detail with subcellular resolution.
“This study provides a strong framework and foundation for us to isolate potential areas where lung injury is affecting normal development and causing it to go off course,” said the paper’s first author, Saahithi Mallapragada, a Ph.D. candidate in the Molecular and Cellular Biology program at Arizona State University. “The spatial context is vital to understanding how a lung becomes capable of breathing — and how that process deviates in premature infants. We can build upon this work and hopefully identify targets that can induce healing and recovery in cases of neonatal lung injury.”
Dr. Nicholas Banovich, TGen
Traditionally, lung injury has been studied by comparing “disease” samples with “controls,” but this approach breaks down when studying premature birth, because infants born early have underdeveloped lungs that aren’t ready to take in oxygen. Any exposure to the outside atmosphere early enough in an individual’s life damages lung tissue heavily, sometimes past the point where recovery can happen.
To overcome this challenge, the investigators developed a new analysis framework that veers away from standard control vs. disease-style experiments and models lung development and dysregulation with only two objective measures — gestational age (time spent in utero) and life span (time after birth until an infant passes away). This method allowed the scientists to study how development and injury intersect and what the effect of time has on both factors, without imposing artificial categories.
“Premature birth changes the developmental trajectory of the lung in complex ways,” said Nicholas Banovich, Ph.D., an associate professor at TGen and a senior author of the study. “By stepping away from rigid disease labels, we can start to see the real spectrum of changes and identify patterns that might point to new treatment targets.”
Mapping Cellular Neighborhoods
Within each lung sample, the researchers identified 40 distinct cell populations — across the epithelial, endothelial, mesenchymal, and immune lineages — and mapped their stage-specific relationships. The atlas they created with these data captures the spatial relationships between certain cell types and their proximity to one another. For example, they found compelling evidence that alveolar type 1 cells and capillaries gradually move closer together as the lung matures to enable efficient gas exchange, confirming a phenomenon seen previously in non-human animal models.
The team also defined 11 distinct niches — regions of cellular and molecular similarity – across the sample cohort. Some niches, like the alveolar niche, expanded steadily through gestation, while others shifted dramatically in rare lung diseases.
Overall, the study found that both gestational age and life span independently influence gene expression in lung cells — and that these molecular changes do not always match what happens in healthy in utero development. Prolonged exposure of the preterm lung to oxygen and mechanical ventilation, for example, may activate genes usually linked to later developmental stages or even stress responses. By comparing gene expression patterns with tissue architecture and a newly created disease severity score, the researchers identified genes and pathways that may serve as potential therapeutic targets to promote healthy lung growth in premature infants.
The complete dataset is now freely available through the Neonatal Lung Spatial Cell Atlas, offering a valuable resource for researchers studying developmental lung biology and dysregulation.
“By making this atlas public, we hope to accelerate the pace of discovery and open new avenues for preventing or repairing injury in the most vulnerable patients — premature infants,” said Jennifer Sucre, M.D., a physician-scientist at Vanderbilt University Medical Center and co-senior author of the study.
The findings were published in the American Journal of Physiology-Lung Cellular and Molecular Physiology.
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About TGen, part of City of Hope
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results. TGen is part of City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes and infectious diseases through cutting-edge translational research (the process of rapidly moving research toward patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and complex rare diseases in adults and children. Working with collaborators in the scientific and medical communities worldwide, TGen makes a substantial contribution to help patients through efficiency and effectiveness of the translational process.
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SOURCE: https://www.tgen.org/news/researchers-map-cellular-landscape-of-the-developing-human-lung/