Researchers at the Perelman School of Medicine at the University of Pennsylvania have produced a detailed molecular atlas of lung development, which is expected to be a fundamental reference in future studies of mammalian biology and new treatments for diseases. , such as COVID-19, that affects the lungs.
The researchers, who published their study in Science, has created an extensive atlas of cell types in developing and adult mouse lungs by measuring the expression of genes in thousands of individual mouse lung cells over their lifetime, covering several cell types and stages of maturity , from early developmental development to adulthood. Analyzing all these data, they predicted thousands of signal interactions among different cell types in the developing lung, confirmed many of these by function tests, and identified several cells and molecular regulators that are critical for normal lung development.
“This study provides institutional information to guide our understanding of how lung activity develops, and how the early postnatal life cycle is a time of rapid change in the lungs to exchange gas. the study’s chief investigator Edward Morrisey, PhD, said the Robinette Professor of Medicine, professor of Cell and Developmental Biology, and director of the Penn-CHOP Institute of Lung Biology at Penn Medicine.
The value of new data appears to be valuable in developing future treatments for early-life lung problems, including adequate lung development in premature infants. It could also find a way to find better treatments for asthma and obstructive pulmonary disease (COPD), two of the leading causes of death worldwide.
The study focused mainly on the developmental stages that led to alveoli maturation. These delicate sac-like structures in the lungs contain thin, capillary-filled limbs that direct the exchange of carbon dioxide into the bloodstream for oxygen in incoming air. The average human lung contains hundreds of millions of alveoli, and the total surface area of their gas exchange organs is estimated to be equal to that of a tennis court.
Many human diseases, from birth to old age, disturb these vital structures. But the information on how cells appear and signal to each other to produce alveoli early in life has remained largely a mystery.
The Morrisey team used two relatively new methods called single-cell RNA sequencing and single-cell ATAC sequence to record the expression and access of genes in thousands of individual cells at seven different time points during lung development. in mice.
They then analyzed gene activity in each cell type, at each time point, to predict which cells were producing important signal molecules and which were the receptors that received these signals. . In this way they mapped projected interactions among these cells, from which they would identify key factors in alveolar development. Finally, they tested the activity of two of these pathways, the Wnt and Sonic Hedgehog (Shh) pathways, using genetic mouse models to execute the action in specific cell types identified in the single-cell experiments.
A recent finding of the study was the identification of a cell type called alveolar epithelial cell type 1 (AT1), which was already known to help create an alveolar gas exchange interface, as a critical initiator and medium of molecular signals that guide alveolar development. . The researchers also concluded that another cell called secondary signaling myofibroblast (SCMF) plays a key role in guiding the maturation of alveolar structures.
In addition, Morrisey’s team identified several transcription factor proteins – which regulate gene activity – as essential for normal alveolar development. Some of these findings have also been proven to occur in human pediatric lungs. The large new database created by the researchers should inform many future studies, including in-depth studies of human lung development.
Molecular details of how alveoli develop will also inform future research aimed at treating disorders that affect these structures. Babies born prematurely often suffer from respiratory distress because their alveoli are not yet fully developed. Pneumonias, which can be caused by bacteria or viruses – including SARS-CoV-2 – and can affect anyone from childhood to old age, are usually ‘reveals a storm of immune molecules and immune cells that damage the alveoli, and destroy the alveolar. gas-exchange interface. Similarly, COPD, which may result from long-term cigarette smoking, involves persistent inflammation and deterioration of alveolar structures.
We hope that our study will provide a framework for a better understanding of the molecular pathways that can be used to promote lung regeneration after traumatic or traumatic injury. “
Edward Morrisey, PhD, Principal Investigator Review
Source:
University of Pennsylvania School of Medicine