Blue cells with yellow spots releasing smaller yellow dots.
Pulmonary ionocytes contain specialized apical caps (yellow) enriched in CFTR and other channels that mediate salt absorption and secretion in the airway to control airway surface liquid volume.
Feng Yuan

Five years ago, researchers discovered a rare cell type in the lungs: pulmonary ionocytes.1 Although ionocytes account for only one percent of all cells lining the airway epithelium, they have the highest expression of cystic fibrosis transmembrane conductance regulator (CFTR), a protein that shuttles water and salt across the lung surface.2 In a recent study published in Nature, researchers used an uncommon animal model, the ferret, to show that ionocytes control airway function.3 The findings have important implications for cystic fibrosis therapeutics.  

Transgenic mice are the gold standard for disease models, but researchers studying cystic fibrosis struggled to recapitulate key phenotypes. “We had to have newer models,” said John Engelhardt, a geneticist at The University of Iowa. He turned to ferrets, whose lung biology and anatomy more closely resembles humans, in the late 1990s, and found that they develop spontaneous bacterial colonization in the airways, a hallmark of cystic fibrosis.4

To determine whether these CFTR-rich cells are the lung’s airway traffic controllers, Engelhardt’s team developed transgenic ferret models to track, tweak, and delete ionocyte function, which helped them identify the mechanisms by which ionocytes regulate airway surface fluid volume, viscosity, and clearing. In his favorite experiment, Engelhardt’s team used single-cell imaging to visualize ionocytes trafficking anions through CFTR portals. “That approach is very powerful moving forward to identify things we didn't even discover within the paper that are still unknown about ionocyte function,” said Engelhardt.

“This paper is really a landmark paper and a technical tour de force,” said Darrell Kotton, a cell biologist at Boston University who was not involved in the study. “It really sets the bar very high for what ionocytes are doing in human lungs and really refocuses our attention on whether the cystic fibrosis drugs might be tailored to modulate ionocytes.”


  1. Montoro DT, et al. Nature. 2018;560:319-324.
  2. Plasschaert LW, et al. Nature. 2018;560:377-381.
  3. Yuan F, et al. Nature. 2023;621:857-867.
  4. Keiser NW, Engelhardt JF. Curr Opin Pulm Med. 2011;17(6):478-483.