Progress towards regenerative therapies for the cystic fibrosis lung and pancreas: insights from stem cells and organoids.

Cystic fibrosis (CF), caused by mutations in the CFTR gene, is characterised by progressive dysfunction in multiple organs. The lung and pancreas largely define patient morbidity and survival, even in the era of highly effective modulator therapies. In the pancreas, CFTR activity loss obstructs exocrine ducts, leading to acinar atrophy and secondary β-cell dysfunction, culminating in CF-related diabetes. In the lung, impaired CFTR-mediated ion transport disrupts mucociliary clearance, driving chronic infection, inflammation, and airway remodelling. Despite these organ-specific manifestations, both tissues share a developmental origin and rely on resident stem and progenitor populations for postnatal maintenance and repair. Human pluripotent stem cells, including patient-derived induced pluripotent stem cells (hiPSCs), have enabled in vitro modelling of lung and pancreatic development. In CF, these models have demonstrated cell-type-specific CFTR defects and facilitated functional testing of modulators. Airway and pancreatic organoids support disease modelling and serve as preclinical platforms for gene correction and pharmacologic intervention. Recent studies highlight the potential of basal airway stem cells, alveolar type 2 cells, and pancreatic progenitors as targets for regenerative or cell-based therapies. Achieving durable organ repair, however, requires coordinated restoration of CFTR function, modulation of inflammation, and maintenance of tissue niches. These advances mark a shift in CF regenerative medicine, emphasising that therapeutic efficacy depends not only on replacing specific cell types, but on restoring a functional, CFTR-competent tissue microenvironment. Integrating these insights provides a roadmap for developing regenerative strategies capable of preserving both respiratory and metabolic functions, improving long-term outcomes for all people with CF.