The researchers, who published their study in Science, generated a broad atlas of cell types within the developing and adult mouse lung by measuring the expression of genes in thousands of individual mouse lung cells across the lifespan, covering multiple cell types and stages of maturation, from early development within the womb to adulthood. Analyzing all this data, they predicted thousands of signaling interactions among different cell types within the developing lung, confirmed many of those with functional experiments, and identified several cells and molecular regulators that are critically important for normal lung development.
“This study provides foundational information to guide our understanding of how lung function develops, and the way the first postnatal period of life may be a time of rapid adjustment within the lungs to optimize gas exchange,” said study senior investigator Edward Morrisey, PhD, the Robinette Foundation Professor of drugs , a professor of Cell and Developmental Biology, and director of the Penn-CHOP Lung Biology Institute at Penn Medicine.
The trove of latest data is probably going to be valuable within the development of future treatments for early-life lung problems, including insufficient lung development in premature babies. it’s going to also speed the look for better therapies for pneumonia and chronic obstructive pulmonary disease (COPD), two of the leading causes of death worldwide.
The study focused largely on the developmental steps resulting in the maturation of alveoli. These delicate sac-like structures within the lungs contain thin, capillary-rich membranes that orchestrate the exchange of CO2 within the bloodstream for oxygen in inhaled air. There are many alveoli in a mean human lung, and therefore the total area of their gas-exchange membranes has been estimated as approximately an equivalent as a tennis court’s.
Many human diseases, from birth to adulthood , disrupt these vital structures. Yet the small print of how cells emerge and signal to every other to cause the formation of alveoli in youth have remained largely mysterious.
Morrisey’s team used two relatively new techniques called single-cell RNA sequencing and single cell ATAC sequencing to record the expression and accessibility of genes in thousands of individual cells at seven different time-points during lung development in mice. They then analyzed the gene activity in each cell type, at whenever point, to predict which cells were making important signaling molecules and which were expressing the receptors that receive those signals. during this way they made a map of predicted interactions among of these cells, from which they might identify key factors in alveolar development. Lastly, they confirmed the activity of two of those pathways, the Wnt and Sonic Hedgehog (Shh) pathway, using genetic mouse models to inactivate their function in specific cell types identified within the single cell experiments.
A novel finding of the study was the identification of a cell type referred to as the alveolar type 1 somatic cell (AT1), which was already known to assist form alveolar gas exchange interface, as an important originator and hub of molecular signals that guide alveolar development. The researchers also determined that another cell type referred to as the secondary crest myofibroblast (SCMF) plays a key role in guiding the maturation of alveolar structures. Morrisey’s team moreover identified several transcription factor proteins — which regulate gene activity — as crucial for normal alveolar development. a number of these findings were also confirmed to occur within the human pediatric lung. The vast new dataset generated by the researchers should empower many future studies, including deeper studies of human lung development.
The molecular details of how alveoli develop also will inform future research aimed toward treating disorders that affect these structures. Babies that are born very prematurely often suffer from respiratory distress because their alveoli aren’t yet fully developed. Pneumonias, which may be caused by bacteria or viruses — including SARS-CoV-2 — and may affect anyone from childhood to adulthood , usually feature a storm of alveoli-damaging immune molecules and immune cells, and therefore the destruction of the alveolar gas-exchange interface. Similarly, COPD, which may result from long-term cigarette smoking, involves chronic inflammation and degeneration of alveolar structures.
“We are hopeful that our study will provide a framework for a far better understanding of the molecular pathways that would be harnessed to market lung regeneration after acute or chronic injury,” Morrisey said.