“We’ve uncovered a whole distribution of cell types that seem to be functionally relevant. The data is starting to change the way we think about lung diseases such as cystic fibrosis and asthma.”
After years and years of studying the CFTR (cystic fibrosis transmembrane conductance regulator) gene and progress in the treatment of cystic fibrosis, researchers still have not been able to find a cure for the disease. But now, based on the findings of two independent studies, they are moving one step closer.
Two research teams have come forward in their discovery of a new type of cell – one that is found in the human airway. One of the teams was comprised of experts from Harvard Medical School and the Novartis Institutes for Biomedical Research (the first study), while the other team was comprised of researchers from Harvard Medical School based at Massachusetts General Hospital and experts at the Broad Institute of MIT and Harvard (the second study). They discovered that a small cell population seems to stimulate the activity of CFTR, which in turn, can lead to the accumulation of thick and sticky mucus in the lungs. This issue, as well as other symptoms, reflects the onset of cystic fibrosis.
The cell population, dubbed “pulmonary ionocytes”, may serve as potential targets for therapeutic approaches against the hereditary disease down the road. “As researchers work toward cures for cystic fibrosis, knowing you are looking at 1% of the cell population seems essential for any type of trouble shooting to improve a therapy or develop new therapies” said Dr. Allon Klein, lead author of the first study and assistant professor of systems biology at the Harvard Medical School.
The researchers’ findings also revealed the traits of types of cells that have been poorly understood until now, thereby extending the current knowledge on airway function and lung disease. “Cystic fibrosis is an amazingly well-studied disease, and we’re still discovering completely new biology that may alter the way we approach it. We have the framework now for a new cellular narrative of lung disease” said Jayaraj Rajagopal, one of the researchers involved in the second study and professor of medicine at Harvard Medical School at Massachusetts General Hospital.
Functional implication of airway - surface regulation
By means of a single-cell sequencing technique, the two research teams intended to build a map of the cells that comprise of the airway. They analyzed the gene expression of thousands of cells in both human and mouse airway models, observing one cell at a time.
By comparing the cell patterns, the researchers created a guideline that listed the different types of cell types, as well as their volume and distribution. And in this way, they were able to pinpoint both known and previously unknown types of cells.
One new type of cell – pulmonary ionocytes – caught their interest. This type of cell revealed a remarkably higher percentage of the CFTR gene. For quite some time now, it was believed that this gene expresses itself at low levels of ciliated cells – a common type of cell in the airway that aims to eliminate foreign invaders. Yet, based on the recent findings, the activity of CFTR occurring in the pulmonary ionocytes accounts for 1% of the cells in the airway. Additionally, the activity of this gene was found to be linked to the number of pulmonary ionocytes in the airway tissue. “With single-cell sequencing technology, and dedicated efforts to map cell types in different tissues, we’re making new discoveries -- new cells that we didn’t know existed, cell subtypes that are rare or haven’t been noticed before, even in systems that have been studied for decades” said Aviv Regev, one of the researchers involved in the second study and professor of biology at MIT.
The researchers involved in the first study found that out of all the actions for constructing the tunnels seen in the samples of mouse cells, 54% derived from ionocytes. And the researchers involved in the second study found that out of all the actions for constructing the tunnels seen in the samples of human cells, ionocytes accounted for 60% of the activity.
While observing the process of this new type of cell in mouse models, the researchers involved in the second study uncovered key characteristics relating to the onset of cystic fibrosis. More specifically, the formation of dense mucus. This led them to derive to the conclusion that by increasing the number of pulmonary ionocytes, the quantity of CFTR activity is increased as well. And by identifying these cells, experts could be guided to use gene therapy in a specific way that would correct unwanted CFTR mutations. “We can use this information to be a bit more clever when we devise therapeutic approaches to cystic fibrosis” said Aron Jaffe, one of the researchers involved in the first study and director at the Novartis Institutes for Biomedical Research.
Shedding new light and insights
Both research teams also characterized changes to certain types of cells during development and after injury. For instance, the research team involved in the first study identified the ‘after injury’ issue by focusing their attention on tracheal regeneration. Using the single-cell sequencing technique in several areas throughout the regeneration process, they monitored how the types of cells specific to injury responded over time. Conversely, the research team involved in the second study identified the ‘during development’ issue by monitoring the development of types of cells from their predecessors (in the mouse models). Using a new technique known as pulse sequence, they revealed how mature cells found in the airway actually develop from a common predecessor – basal cells.
According to the researchers, a map of the types of cells and their activity in normal states, during the development process and during the regeneration process, could prove to be helpful for future investigations on diseases, like cystic fibrosis. In fact, Regev, Rajagopal, and their fellow colleagues exposed a gene associated with the development of asthma by ciliated cells, as well as by tuft cells. These findings allowed them to distinguish two separate groups – both aimed at a better understanding of the disease with the right targeted treatment. “We’ve uncovered a whole distribution of cell types that seem to be functionally relevant. What’s more, genes associated with complex lung diseases can now be linked to specific cells that we’ve characterized. The data are starting to change the way we think about lung diseases such as cystic fibrosis and asthma” said Rajagopal.