During the last trimester of pregnancy, the developing lung is particularly vulnerable to being permanently damaged by increased oxygen exposure and inflammation that can result from an extremely premature birth.
To find out why, researchers at Vanderbilt University Medical Center have constructed a single-cell “atlas” of lung development in the mouse that tracks multiple cell types over time.
Using a technique called single-cell RNA-sequencing, or scRNA-seq, the researchers followed more than 100,000 cells from embryonic day 12 to postnatal day 14 in the mouse. The result, reported Dec. 20 in the journal Development, is the longest and most detailed “developmental roadmap” of the lung achieved to date.
“This study provides a granular, cell-specific understanding of the stages of lung development and discovers that each cell type matures along a specific timeline,” said Jennifer Sucre, MD, the paper’s co-corresponding author with Jonathan Kropski, MD. “Our analysis tools allow us to predict cell-fate determination and to generate hypotheses about the specific vulnerability of the developing lung to injury.”
Among their findings, the researchers describe a previously unrecognized role of alveolar type 1 (AT1) pneumocyte cells in establishing the extracellular matrix scaffold of the developing lung.
“These data suggest that AT1 cells, which for a long time were believed to serve as little more than a surface for gas exchange, actually play a major role in establishing the structure of the developing alveolus,” Kropski said.
Overall, the transition from the saccular stage, when the air sacs begin to take shape, to the development of the alveoli, which enable the exchange of carbon dioxide and oxygen from air to bloodstream, appears to be fluid and highly cell-type specific.
The dynamic expansions and contractions of different cell populations suggest that there is tremendous coordination and interaction at every time point. “It appears that many cell types in the lung possess the ability to signal to each other during key transitional periods,” the researchers concluded.
The atlas provides a foundation for future mechanistic studies into pathways that govern coordinated cell-to-cell communication across this specialized stage of lung development.
Better understanding of the complexity of normal development could lead to new ways to intervene to prevent lung damage that can result from extremely premature birth or infections that occur later in life.
Sucre, assistant professor of Pediatrics, and Kropski, associate professor of Medicine, have secondary appointments in the Department of Cell and Developmental Biology. The paper’s first authors are Nicholas Negretti, PhD, Erin Plosa, MD, and John Benjamin, MD, MPH.
Co-authors are Bryce Schuler, MD, PhD, A. Christian Habermann, Christopher Jetter, Peter Gulleman, Claire Bunn, Alice Hackett, MD, Meaghan Ransom, MD, MPH, Chase Taylor, David Nichols, Brittany Matlock, Susan Guttentag, MD, and Timothy Blackwell, MD.
The research was supported in part by National Institutes of Health grants HL143051, HL130595, HL153246, HL145372, HL092470, HL127102, HL154287, HL133484 and HL157373, and the Francis Family Foundation.