Investigators from the Broad Institute of MIT and Harvard and Massachusetts General Hospital (MGH) have discovered a rare cell type in airway tissue that appears to be a key player in the biology of cystic fibrosis.
The discovery of the cell, Foxi1+
pulmonary ionocyte, establishes the framework for a new cellular narrative for the rare neurodegenerative disease and offers critical insight into the disease’s underlying genetic basis. By explaining the key role of the rare cell in the disease’s biology, investigators provide further insight that can be used to inform the development of targeted cystic fibrosis therapies.
"We've uncovered a whole distribution of cell types that seem to be functionally relevant," said Jayaraj Rajagopal, MD, who is also a professor at Harvard Medical School and a principal faculty member at the Harvard Stem Cell Institute, in a recent statement
. "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 like cystic fibrosis."
In an effort to better understand what goes awry in the rare disease’s underlying biological functions, the MIT and MGH teams used single-cell RNA sequencing to analyze tens of thousands of cells from the airway in mouse models, charting the physical locations of cell types and mapping a cellular "atlas" of the tissue. To monitor development of cell types from their progenitors in the mouse airway, the team also created a new method referred to as pulse-seq, which combined scRNA-seq with lineage tracing. Through this method, the investigators were able to show that tuft, neuroendocrine, and ionocyte cells are continually and directly replenished by basal progenitor cells. The findings
were further validated in human 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, PhD, director of the Klarman Cell Observatory at the Broad Institute, professor of biology at MIT, and an HHMI investigator, supervised the research. "And for some of these, understanding and characterizing them sheds new light immediately on what's happening inside the tissue."
The investigators noted that compared with other known cells in the dataset, 1 extremely rare cell type that made up less than 1% of the cell population in mice and humans appeared to be radically different. Due to the fact that this cell’s gene expression pattern was similar to that of ionocytes, which are specialized cells that control ion transport and hydration in fish gills and frog skin, the team labeled the cell the "pulmonary ionocyte.”
The team documented that these ionocytes expressed the CFTR
gene at higher levels than any other cell type, which is important because when the CFTR
gene is mutated, cystic fibrosis is caused in humans. Furthermore, the CFTR
gene is crucial for airway function. While clinicians and investigators previously believed CFTR
to be regularly expressed at low levels in ciliated cells, this new data suggests that the majority of CFTR
expression occurs in only a few cells, cells that were not known to even exist until now.
“It [the discovery of the Foxi1+
pulmonary ionocyte cells] has to change the way we think about what is going wrong in this disease,” said Dr Rajagopal in an exclusive quote to Rare Disease Report®
. “How could a rare cell type have such a big impact? Also, if we want to cure the disease, we will have to fix this particular cell type, make more of it, or do both. Hopefully, the ionocyte will express other target proteins of therapeutic value, but the most obvious implication is that it reframes the way we have to think about curative gene therapy approaches. I am sure cystic fibrosis biologists will find many more interesting things to consider based on their deeper expertise.”
With this data, the team believes there may also be substantial implications for developing targeted cystic fibrosis therapies, such as gene therapy that corrects for a mutation in CFTR.
However, such a treatment
would need to be delivered to the right cells, and, as such, a “cell atlas” of the tissue could provide a “reference map” to guide that process. The investigators were able to identify other disease-associated genes that were expressed in the airway.
Using the pulse-seq assay, the teams were able to track how the new cells and subtypes in the mouse airway develop. They found that the basal cells serve as the common progenitor, and many of the mature cells in the airway arise from these cells. They also discovered what they referred to as “hillocks,” which are cellular structures that serve as unique zones of rapid cell turnover. Previous to this research, these structures were previously undescribed in the literature; as such, their function is not well understood. The findings expand scientific and clinical understanding of lung biology, with broad implications for all diseases of the airway—not just cystic fibrosis.
"The atlas that we've created is already starting to drastically re-shape our understanding of airway and lung biology," added Dr Regev. "And, for this and other organ systems being studied at the single-cell level, we'll have to drape everything we know on top of this new cellular diversity to understand human health and disease.”