Faculty : Departmental- Primary

Nevis L. Fregien, Ph.D.

Research in my laboratory focuses on understanding the molecular control of commitment, differentiation and replacement of ciliated epithelial cells in the airway. Every breath we take exposes our airway and lungs to noxious and pathogenic agents from the environment. A pseudostratified epithelium lining the respiratory tract provides the first line of defense. This epithelium contains many different cell types including ciliated, basal, goblet and Clara cells that work in concert to protect the airway by mucociliary clearance (MCC). Secretory cells emit sticky, viscous mucus that entraps invading particles while the wave-like beating of the cilia on ciliated cells propels the mucus with the trapped particles out of the airway. The ratio of secretory to ciliated cells is critical to ensure maximal MCC efficiency and a healthy airway. The balance of ciliated and secretory cells is established during embryogenesis. These cell types differentiate from common progenitors of the foregut endoderm during lung development. The time that cell fates are determined is not clear, but the differentiation of each cell type is most likely influenced by many factors including cell-cell interactions and growth factor signaling that modulate the expression of cell specific transcription factors and genes that carry out differentiated cell-specific functions. In many airway pathologies, including asthma and smoke exposure, the ratio of ciliated to secretory cells decreases and MCC efficiency decreases due to insufficient numbers of cilia to efficiently propel the increasing mucus layer and ensnared noxious particles out of the airway, resulting in the accumulation of mucus in the airway and disease progression. Understanding the molecular basis for the loss of ciliated cells is not fully understood, but minimizing or preventing ciliated cell loss could be of great therapeutic benefit.

My laboratory is focused on characterizing the molecular events that control the commitment, differentiation and regeneration of ciliated cells in the airway. Our studies are centered on the expression of the FoxJ1 gene. The expression of this gene is tightly controlled during ciliated cell differentiation, precedes the expression of the ciliated phenotype, and is required for ciliogenesis. We use primary normal human airway epithelial cells for these experiments because they can be de-differentiated and redifferentiated in vitro, using air:liquid interface culture conditions. We have recently found that FoxJ1 expression is linked to the formation of apical junctions. Based on these results, we propose a novel signaling pathway between junction formation and FoxJ1 transcription to control ciliogenesis.

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Figure 1. AJC formation in NHBE cells. Transwell cultures of NHBE cells were plated in BEGM medium. The next day, samples were fed :A, BEGM; B, ALI medium; and C, BEGM medium + 0.25 mM Ca2+. Cells were incubated overnight, fixed and AJC stained with anti-ZO-1 (Alexa 488, Green channel) and anti-FOXJ1 (Alexa 555, red channel). All micrographs were imaged with identical settings. ZO-1 is assembled into AJC upon a switch to high Ca2+ containing media. However, FOXJ1 expression is only detectable in the fully differentiated cells (panel D).

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Figure 2. Diagram of ciliated cell differentiation and loss of ciliated cells in disease.

Select Publications

  • Horvath, G., Mendes, E.S., Schmid, N., Conner, G.E., Fregien, N.L., Salathe, M., Wanner, A. Rapid nongenomic actions of inhaled corticosteroids on long-acting β(2)-agonist transport in the airway. Pulm Pharmacol Ther. 2011 Sep 9 [Epub ahead of print] PMID: 21914487.
  • Schmid, A., Sutto, Z., Schmid, N., Noak, L., Ivonnet, P., Horvath, G., Conner, G, Fregien, N.L., Salathe, M. Decreased soluble adenylyl cyclase activity in cystix fibrosis is related to defective apical bicarbonate exchange and affects ciliary beat frequency regulation. J Biol Chem. 2010 Sep 24; 285(39):29998-3007. PMID: 20639512
  • Monzon, M.E., Fregien, N.L., Schmid, N., Falcon, N.S., Campos, M., Casalino-Matsuda, S.M., Forteza, R.M. Reactive oxygen species and hyaluronidase 2 regulate airway epithelial hyaluronan fragmentation. J Biol Chem. 2010 Aug 20; 285(34):26126-34. PMID: 20554532.

View published research articles by Dr. Fregien in the National Library of Medicine.