A deeper understanding of cystic fibrosis

August 1, 2018

Researchers find a new type of lung cell involved in cystic fibrosis

Rajagopal ionocyte cystic fibrosis Nature 2018
The newly identified ionocytes (orange) in the mouse airway. (Montoro et al./Nature 2018)

By Jessica Lau

In cystic fibrosis, mucus builds up in the lungs and leads to breathing difficulties because cells do not properly make the CFTR protein. Although scientists have known for decades that the defective CFTR gene causes cystic fibrosis, it has been unclear which specific cells are responsible for making CFTR in the first place.

In a new study published in Nature, researchers at the Broad Institute, Massachusetts General Hospital (MGH), and the Harvard Stem Cell Institute (HSCI) identified a new type of lung cell — the ionocyte — that contributed to most of the CFTR gene expression in healthy mouse and human airways.

Jayaraj Rajagopal, M.D. and Aviv Regev, Ph.D. were the co-senior authors of the study. Rajagopal is a Professor of Medicine at Harvard Medical School, a physician in the Pulmonary and Critical Care Unit at MGH, an associate member at the Broad Institute, and a Principal Faculty member at HSCI. Regev is a Professor of Biology at the Massachusetts Institute of Technology and a core member at the Broad Institute.

The researchers used single-cell sequencing technology to measure gene expression in the mouse airway. By analyzing tens of thousands of individual cells, they built a detailed catalog of many different cell types.

They identified a new and rare cell type where CFTR gene expression was concentrated, which they named the ionocyte. The researchers found CFTR-expressing ionocytes in both mouse and human tissue.

To further test that ionocytes are involved in cystic fibrosis, the researchers disrupted those specific cells in mice. Without functional ionocytes, the mice showed symptoms of cystic fibrosis such as highly viscous mucus.

In addition to focusing on ionocytes and their role in cystic fibrosis, the researchers used their comprehensive catalog of airway cells to characterize new structures in airway tissue and to investigate genes involved in other lung diseases such as asthma.

“The discovery of the ionocyte is a surprising finding that gives us a new way of looking at cystic fibrosis,” said Carla Kim, Ph.D., a member of HSCI Executive Committee who studies lung stem cell biology. She was not involved in the present study. “The paper describes a number of new cell types, which is important for understanding both normal lung biology and lung diseases.”

“This study is a great example of the unique environment of HSCI,” said Kim. “We’re in Boston and Cambridge where we can collaborate with scientists like Aviv Regev — an expert in single-cell sequencing — whose technology enabled these findings to happen.”

About the study

Montoro D.T., Haber A.L., Biton M. et al. (2018). A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature. DOI: 10.1038/s41586-018-0393-7

Broad Institute News (2018). Researchers discover new type of lung cell, critical insights for cystic fibrosis.

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An independent study by researchers from Harvard Medical School and Novartis Institutes for Biomedical Research corroborates the findings and is published concurrently in Nature. The study was led by Allon Klein, who is an HSCI Affiliate Faculty member, and Aron Jaffe.

Plasschaert L.W., Žilionis R. et al. (2018). A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature. DOI: 10.1038/s41586-018-0394-6

The Harvard Gazette (2018). Cystic fibrosis cure may be found in newly identified cell type.