BREATH scientists are on the trail of primary ciliary dyskinesia

Progress brings an in vitro model of the airway epithelium based on human induced pluripotent stem cells


Primary ciliary dyskinesia (PCD) is a rare, heterogeneous genetic disorder with far-reaching consequences. There has not yet been a decisive breakthrough in the therapy, as the correlations are complex and cell material sparse. A major step in the right direction has now been successful in the working group led by the BREATH scientist, Dr. Ruth Olmer, at the Leibniz Research Laboratory for Biotechnology and Artificial Organs (LEBAO) at Hannover Medical School. Laura von Schledorn, a doctoral student in this working group, has been able to demonstrate in an in vitro model for PCD with ciliated airway epithelial cells, on the basis of human induced pluripotent stem cells (hiPSC) in the air-liquid interface cell culture models, connections between mutations in the DNAH5 and NME5 genes with the afflicted phenotype.

The dysfunction of moving cilia in the airways occurring in the PCD is accompanied by a reduced mucociliary clearance. Pathogenic germs establish themselves in the respiratory tract and induce chronic inflammation of the airways, which finally leads to a progressive destruction of pulmonary tissue. Despite the great medical need and intensive research in this area, up to now there is no curative therapy available for PCD. For some time, however, effective therapeutic principles have been sought.  Laura von Schledorn has looked into the this challenge using an in vitro model, based on airway epithelium in air-liquid interface cell culture models, derived from human induced pluripotent stem cells (hiPSC). These cells can be increased indefinitely in the laboratory and differentiate into ciliated airway epithelial cells.

Using transmission electron microscopy, immunofluorescence staining, measurement of the cilial pulse rate and the mucociliary transport, Laura von Schledorn was able to show that airway epithelium covered with cilia, derived from hiPSC from PCD patients, who carry mutations in the DNAH5 and NME5 genes, reflects the disease phenotype on the molecular, structural and functional level.

Focus on cilia research

Up to now, PCD-inducing mutations have been found in more than 50 genes, resulting in various functional defects, from abnormal frequency of the heartbeat to the complete absence of cilia. Depending on the underlying mutation, congenital heart diseases and reduced fertility may occur. Current PCD research is focussed on the identification of these disease-causing mutations. With the work discussed here, it has been possible to establish an in vitro disease model for PCD, which reflects the disease phenotype on a molecular and functional level. „With the successful establishment of the model, we now have a platform which allows us to further explain the patient-specific pathomechanisms, to test the effectiveness of innovative therapeutic approaches and identify new potential therapeutics within the scope of high throughput screening, Laura von Schledorn explains. Whether a clinically relevent breakthrough in PCD research will be achieved in the next few years seems, however, questionable. Although research in the past few years  has already identified a number of PCD-relevant genes, PCD diagnostics remains a lengthy process and therapeutic possibilities continue to be insufficient.  Due to the genetic heterogeneity of the disease, development of a generally effective curative therapy is probably not realizable, according to Dr. Ruth Olmer. „We are, however, optimistic that, with the aid of complex disease models, the understanding of basic pathomechanisms and the development of reliable diagnostic methods will be advanced and the identification and validation of therapeutics made possible, so that eventually the path towards personalized medicine will be paved smoothly.“

The results have been published in the renowned specialist journal Cells:
von Schledorn, L.; Puertollano Martín, D.; Cleve, N.; Zöllner, J.; Roth, D.; Staar, B.O.; Hegermann, J.; Ringshausen, F.C.; Nawroth, J.; Martin, U.; et al. Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro. Cells 2023, 12, 1467. .  

Text: BREATH AZ/ L. von Schledorn
Photo: L. von Schledorn

Laura von Schledorn at the lab bench