Cystic fibrosis is a genetic disease caused by dysfunction of the CFTR protein. This defect leads to viscous mucus in the airways, impairs ciliary activity, and promotes recurrent infections as well as progressive deterioration of lung function. While effective CFTR modulator therapies are now available for patients with the most common CFTR mutation, individualized treatment options are still lacking for individuals with rare and currently non-treatable mutations. At the same time, classical in vitro models such as intestinal organoids or primary airway epithelial cells reach their limits when it comes to realistically modeling the complex mechanisms underlying mucociliary dysfunction.

This is where the new model comes into play. Using human induced pluripotent stem cells (iPSCs) derived from individuals with CF, the researchers generated airway epithelial cells in air–liquid interface cultures (iALI) and were able to reproduce key features of the characteristic functional impairments of CF airways. For functional analyses, they employed an automatable ciliary beat frequency (CBF) assay that precisely quantifies ciliary activity. This readout directly reflects changes in mucociliary transport, which is markedly impaired in CF due to increased mucus viscosity—a central clinical problem of the disease. Validation was performed using established CFTR modulators, which partially corrected the pathological phenotype of the CF-iALI cultures and thus mirrored therapeutic effects known from clinical application.

“Our iPSC-based model enables us, for the first time, to capture the complex functional impairments of the mucociliary system in cystic fibrosis using a reproducible and patient-specific approach. This not only provides deeper insights into the molecular mechanisms of the disease, but also establishes an important foundation for the development of individualized therapeutic options,” summarizes Dr. Sylvia Merkert, senior author of the study (together with Prof. Dr. Ulrich Martin and Prof. Dr. Markus Mall).

The study addresses key limitations of existing CF in vitro models and demonstrates for the first time that iPSC-based air–liquid interface cultures represent a robust and reproducible system suitable for both basic research and diagnostic applications. The model thus opens up new opportunities to investigate the genetic and molecular mechanisms of CF lung disease with greater precision. At the same time, it provides a promising platform for preclinical drug development and for the personalized testing of potential drug combinations tailored to specific CFTR mutations.

The work entitled “Human induced pluripotent stem cells for in vitro modeling of impaired mucociliary clearance in cystic fibrosis lung disease” was published in the journal Stem Cell Research & Therapy.

Original publication:

Klassen MC, Balázs A, Zöllner J, Cleve N, Czichon L, von Schledorn L, Hegermann J, Nawroth JC, Roth D, Mielenz M, Hedtfeld S, Stanke F, Rubil T, Ius F, Jonigk D, Hanrahan JW, Ruhparwar A, Olmer R, Mall MA, Merkert S, Martin U. Human induced pluripotent stem cells for in vitro modeling of impaired mucociliary clearance in cystic fibrosis lung disease. Stem Cell Res Ther. 2025 Oct 21;16(1):573. doi: 10.1186/s13287-025-04737-0. PMID: 41116195; PMCID: PMC12538740

Text: BREATH/ SM,AB