{"id":8800,"date":"2018-08-02T12:43:15","date_gmt":"2018-08-02T16:43:15","guid":{"rendered":"https:\/\/biology.mit.edu\/?p=8800"},"modified":"2020-10-29T23:14:13","modified_gmt":"2020-10-30T03:14:13","slug":"researchers-discover-new-type-of-lung-cell-critical-insights-for-cystic-fibrosis","status":"publish","type":"post","link":"https:\/\/biology.mit.edu\/researchers-discover-new-type-of-lung-cell-critical-insights-for-cystic-fibrosis\/","title":{"rendered":"Researchers discover new type of lung cell, critical insights for cystic fibrosis"},"content":{"rendered":"
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Researchers have identified a rare cell type in airway tissue, previously uncharacterized in the scientific literature, that appears to play a key role in the biology of cystic fibrosis. Using new technologies that enable scientists to study gene expression in thousands of individual cells, the team comprehensively analyzed the airway in mice and validated the results in human tissue.<\/p>\n

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Led by researchers from the Broad Institute of MIT and Harvard and Massachusetts General Hospital (MGH), the molecular survey also characterized gene expression patterns for other new cell subtypes. The work expands scientific and clinical understanding of lung biology, with broad implications for all diseases of the airway \u2014 including asthma, chronic obstructive pulmonary disease, and bronchitis.<\/p>\n

Jayaraj Rajagopal<\/a>, a physician in the Pulmonary and Critical Care Unit at MGH, associate member at the Broad Institute, and a Howard Hughes Medical Institute (HHMI) faculty scholar, and Broad core institute member\u00a0Aviv Regev<\/a>, director of the\u00a0Klarman Cell Observatory<\/a>\u00a0at the Broad Institute, professor of biology at MIT, and an HHMI investigator, supervised the research. Daniel Montoro, a graduate student in Rajagopal\u2019s lab, and postdoctoral fellows Adam Haber and Moshe Biton in the Regev lab are co-first authors on the paper published today in\u00a0Nature<\/em><\/a>.<\/p>\n

\u201cWe have the framework now for a new cellular narrative of lung disease,\u201d said Rajagopal, who is also a professor at Harvard Medical School and a principal faculty member at the Harvard Stem Cell Institute. \u201cWe\u2019ve uncovered a whole distribution of cell types that seem to be functionally relevant. What\u2019s more, genes associated with complex lung diseases can now be linked to specific cells that we\u2019ve characterized. The data are starting to change the way we think about lung diseases like cystic fibrosis and asthma.\u201d<\/p>\n

\u201cWith single-cell sequencing technology, and dedicated efforts to map cell types in different tissues, we\u2019re making new discoveries \u2014 new cells that we didn\u2019t know existed, cell subtypes that are rare or haven\u2019t been noticed before, even in systems that have been studied for decades,\u201d said Regev, who is also co-chair of the international\u00a0Human Cell Atlas<\/a>\u00a0consortium. \u201cAnd for some of these, understanding and characterizing them sheds new light immediately on what\u2019s happening inside the tissue.\u201d<\/p>\n

Using single-cell RNA sequencing, the researchers analyzed tens of thousands of cells from the mouse airway, mapping the physical locations of cell types and creating a cellular \u201catlas\u201d of the tissue. They also developed a new method called pulse-seq to monitor development of cell types from their progenitors in the mouse airway. The findings were validated in human tissue.<\/p>\n

One extremely rare cell type, making up roughly one percent of the cell population in mice and humans, appeared radically different from other known cells in the dataset. The team dubbed this cell the \u201cpulmonary ionocyte\u201d because its gene expression pattern was similar to ionocytes \u2014 specialized cells that regulate ion transport and hydration in fish gills and frog skin.<\/p>\n

Strikingly, at levels higher than any other cell type, these ionocytes expressed the gene\u00a0CFTR<\/em>\u00a0\u2014 which, when mutated, causes cystic fibrosis in humans.\u00a0CFTR<\/em>\u00a0is critical for airway function, and for decades researchers and clinicians have assumed that it is frequently expressed at low levels in ciliated cells, a common cell type spread throughout the entire airway.<\/p>\n

But according to the new data, the majority of\u00a0CFTR<\/em>\u00a0expression occurs in only a few cells, which researchers didn\u2019t even know existed until now.<\/p>\n

When the researchers disrupted a critical molecular process in pulmonary ionocytes in mice, they observed the onset of key features associated with cystic fibrosis \u2014 most notably, the formation of dense mucus. This finding underscores how important these cells are to airway-surface regulation.<\/p>\n

\u201cCystic fibrosis is an amazingly well-studied disease, and we\u2019re still discovering completely new biology that may alter the way we approach it,\u201d said Rajagopal. \u201cAt first, we couldn\u2019t believe that the majority of\u00a0CFTR<\/em>\u00a0expression was located in these rare cells, but the graduate students and postdocs on this project really brought us along with their data.\u201d<\/p>\n

The results may also have implications for developing targeted cystic fibrosis therapies, according to the team. For example, a gene therapy that corrects for a mutation in\u00a0CFTR<\/em>would need to be delivered to the right cells, and a cell atlas of the tissue could provide a reference map to guide that process.<\/p>\n

The study further highlighted where other disease-associated genes are expressed in the airway. For example, asthma development has been previously linked with a gene that encodes a sensor for rhinoviruses, and the data now indicate that this gene is expressed by ciliated cells. Another gene linked with asthma is expressed in tuft cells, which separated into at least two groups \u2014 one that senses chemicals in the airway and one that produces inflammation. The results suggest that a whole ensemble of cells may be responsible for different aspects of asthma.<\/p>\n

Using the pulse-seq assay, the researchers tracked how the newly characterized cells and subtypes in the mouse airway develop. They demonstrated that mature cells in the airway arise from a common progenitor: the basal cells. The team also discovered a previously undescribed cellular structure in the tissue. These structures, which the researchers called \u201chillocks,\u201d are unique zones of rapid cell turnover, and their function is not yet understood.<\/p>\n

\u201cThe atlas that we\u2019ve created is already starting to drastically re-shape our understanding of airway and lung biology,\u201d said Regev. \u201cAnd, for this and other organ systems being studied at the single-cell level, we\u2019ll have to drape everything we know on top of this new cellular diversity to understand human health and disease.\u201d<\/p>\n

Funding for this study was provided in part by the Klarman Cell Observatory at the Broad Institute, Manton Foundation, HHMI, New York Stem Cell Foundation, Harvard Stem Cell Institute, Human Frontiers Science Program, and National Institutes of Health.<\/em><\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n

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Paper(s) cited:<\/p>\n

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Montoro DT, Haber AL, Biton M et al.\u00a0A revised airway epithelial hierarchy includes\u00a0CFTR<\/em>-expressing ionocytes<\/a>.\u00a0Nature<\/em>. Online August 1, 2018. DOI: 10.1038\/s41586-018-0393-7<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/section>\n","protected":false},"excerpt":{"rendered":"

Researchers have identified a rare cell type in airway tissue, previously uncharacterized in the scientific literature, that appears to play a key role in the biology of cystic fibrosis. 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