The influencers of the lung airway
If cystic fibrosis was a social media platform, pulmonary ionocytes would have been its biggest influencers. Influencers have a considerable sway in a niche area and they have the ability to influence the surrounding environment with a significant impact. Similarly, pulmonary ionocytes are a rare cell type that accounts for approximately 1% of the airway epithelial cells and contribute significantly to the pathogenesis of cystic fibrosis (CF) (1). They were recently identified during single-cell RNA sequencing performed in order to create a “human cell atlas”. These cells have high cystic fibrosis transmembrane conductance regulator (CFTR) protein expression, which, when mutated, causes cystic fibrosis in humans (2). It is a genetic disease caused by a dysfunction in the CFTR anion channel which is responsible for transporting chloride and bicarbonate ions in order to maintain a healthy environment within the lung airway and monitor epithelial cellular activities. CF is characterized by hyperconcentrated mucus and reduced bacterial killing in the airway as a result of defective airway surface liquid (ASL) production. The single-cell based transcriptional data collected by researchers so far suggests the prevalence of pulmonary ionocyte-associated CFTR expression among the airway epithelial cells (3).
Role of pulmonary ionocytes in cystic fibrosis
Pulmonary ionocytes maintain the normal functioning of CFTR anion channel in a healthy individual. CFTRs are found on the apical membrane of the lung airway epithelia and play a critical role in keeping the airway healthy by producing the ASL. The ASL is necessary for mucociliary clearance (MCC) which is a crucial innate defense strategy of the human body to support lung health (4). The mechanism of MCC helps in propelling the pathogens and inhaled particles trapped in the mucous layer out of the airways thus balancing the ASL pH and reducing airway inflammation. Therefore, a defect in the pulmonary ionocytes can perturb the anion transport via CFTRs, thus causing a depletion in the production of ASL, further resulting in abnormal mucociliary transport and intense airway inflammation (5).
Since the identification of pulmonary ionocytes, several investigators have attempted to establish positive correlation between them and the disease. A study by Sato et al., emphasizes on the capacity of ionocytes to mediate chloride secretion in human bronchial epithelial cells despite their rarity (6). In another study by Yuan et al., it has been demonstrated that genetic depletion of ionocytes in tracheal epithelia of a ferret leads to an approximately 70% reduction in CFTR-mediated chloride secretion and mucociliary transport (7). Although pulmonary ionocytes are being investigated extensively, there is a critical need for more evidence to relate the biology of pulmonary ionocytes to the disease’s physiology.
Pulmonary ionocytes in a dish
Regardless of their discovery in 2018, the existence of pulmonary ionocytes was suggested about three decades ago by Engelhardt et al. (8). Ionocytes were first described as chloride secreting cells in gills of eel in the 1930s by Keys and Willmer (9). It was hypothesized that these cells play a primary role in maintaining the ion and fluid homeostasis in fish and amphibians. To further explore and strengthen their role in human health and disease, more evidence was required from biologically similar model systems. A group of researchers at the Boston General Hospital understood the relevance and need of functional human models systems and developed a method for the de novo generation of pulmonary ionocytes from human induced pluripotent stem cells (iPSCs). The iPSC-derived airway basal-like cells were validated with their in vivo counterparts which exhibited the functionality and features of the resident airway stem cells. The pulmonary ionocytes prepared from the scratch were confirmed for their lineages and CFTR expression levels using fluorescent staining techniques. The results obtained from the extensive investigation indicated a successful differentiation of iPSCs into human ionocyte-like populations (10). This method has the potential to become a constant source of pulmonary ionocytes for basic studies towards therapeutics and regenerative medicine applications. That being said and considering the implications, there is yet a lot to be explored in the field of lung physiology and human disease.
Recognizing and appreciating the labs working in this space
- Kotton Lab, Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, Massachusetts, USA. https://www.bumc.bu.edu/kottonlab/
- Vallier Lab, Max Planck Institute for Molecular Genetics, Berlin, Germany. https://www.molgen.mpg.de/4595564/vallier-lab
- Elab — The University of Iowa, Iowa city, Iowa, USA. https://engelhardt.lab.uiowa.edu/about
- The Rajagopal Lab, Center for Regenerative Medicine, Massachusetts General Hospital, Boston. Massachusetts, USA. https://www.rajagopallab.com/
- Klein Lab, Systems Biology Department, Harvard Medical School. Boston, Massachusetts, USA. https://www.klein.hms.harvard.edu/
- Cystic Fibrosis Transmembrane Regulator Function Laboratory — McGill University. Montreal, Quebec, Canada. https://www.mcgill.ca/cftrfunction/
- Juan Ianowski Laboratory, University of Saskatchewan. Saskatoon, Saskatchewan, Canada. https://research-groups.usask.ca/ianowskilab/index.php
- Pulmonary Medicine, Boston Children’s Hospital. Massachusetts, USA. https://www.childrenshospital.org/departments/pulmonary-medicine
- Luis Galietta — TIGEM. The Telethon Institute of Genetics and Medicine, Pazzouli, Italy. https://www.tigem.it/research/research-faculty/galietta
- Research and development, Novartis. Novartis Institute of Biomedical Research. Cambridge, Massachusetts, USA. https://www.novartis.com/research-and-development
References
- Luan, Xiaojie et al. “Pulmonary Ionocytes Regulate Airway Surface Liquid pH in Primary Human Bronchial Epithelial Cells.” American journal of respiratory and critical care medicine vol. 210,6 (2024): 788–800. doi:10.1164/rccm.202309–1565OC
- https://www.broadinstitute.org/news/researchers-discover-new-type-lung-cell-critical-insights-cystic-fibrosis
- Okuda, Kenichi, and Martina Gentzsch. “Pulmonary Ionocytes: What Are They Transporting and Which Way?.” American journal of respiratory and critical care medicine vol. 210,6 (2024): 705–707. doi:10.1164/rccm.202404–0727ED
- Bustamante-Marin, Ximena M, and Lawrence E Ostrowski. “Cilia and Mucociliary Clearance.” Cold Spring Harbor perspectives in biology vol. 9,4 a028241. 3 Apr. 2017, doi:10.1101/cshperspect.a028241
- Ratjen, Felix. “Restoring airway surface liquid in cystic fibrosis.” The New England journal of medicine vol. 354,3 (2006): 291–3. doi:10.1056/NEJMe058293
- Sato, Yukiko et al. “Ionocyte-Specific Regulation of Cystic Fibrosis Transmembrane Conductance Regulator.” American journal of respiratory cell and molecular biology vol. 69,3 (2023): 281–294. doi:10.1165/rcmb.2022–0241OC
- Yuan, Feng et al. “Transgenic ferret models define pulmonary ionocyte diversity and function.” Nature vol. 621,7980 (2023): 857–867. doi:10.1038/s41586–023–06549–9
- Engelhardt, J F et al. “Submucosal glands are the predominant site of CFTR expression in the human bronchus.” Nature genetics vol. 2,3 (1992): 240–8. doi:10.1038/ng1192–240
- Keys, A, and E N Willmer. “”Chloride secreting cells” in the gills of fishes, with special reference to the common eel.” The Journal of physiology vol. 76,3 (1932): 368–378.2. doi:10.1113/jphysiol.1932.sp002932
- Wang, Ruobing et al. “De Novo Generation of Pulmonary Ionocytes from Normal and Cystic Fibrosis Human Induced Pluripotent Stem Cells.” American journal of respiratory and critical care medicine vol. 207,9 (2023): 1249–1253. doi:10.1164/rccm.202205–1010LE
About the author:
DR. SURUCHI PODDAR
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Poddar received a PhD in Biomedical Engineering from Indian Institute of Technology-Banaras Hindu University (IIT-BHU), Varanasi, India. She started her career as a postdoctoral researcher in 2020 with the Nanoscience Technology Center at the University of Central Florida, Orlando where she worked on a multi-organ human-on-a-chip system. Currently she is working on solid-state nanopore technology at Wake Forest University, North Carolina. When not working, she enjoys watching movies, cooking food and exploring new places, restaurants, attractions.
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Alexandra Banbanaste is completing her Master’s in Chemical Engineering at Ecole Polytechnique Fédérale de Lausanne, where she studied neuroscience, chemistry, and biology.
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The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
