Exocrine pancreatic insufficiency (EPI) is a prevalent comorbidity in cystic fibrosis (CF), affecting approximately 85% of CF infants within the first year of life. However, the precise role of CF transmembrane conductance regulator (CFTR) in pancreatic development and the molecular mechanisms by which CFTR mutations contribute to pancreatic insufficiency remain incompletely understood. We have sequenced the developing ferret pancreas covering embryonic development from E24 through E38 and mapped this to existing human pancreatic development data. This data provides evidence for CFTR expression in multipotent pancreatic progenitors (PP) with expression increasing as fate decisions direct cells toward ductal lineages. Given the limited availability of developing pancreatic tissue, induced pluripotent stem cell (iPSC)-derived models provide a powerful in vitro platform for investigating mechanisms of pancreatic development in which CFTR may play a functional role. This study tests the hypothesis that CFTR expression and/or function influences the differentiation and maturation of PP cells. Patient-specific, human-derived iPSCs from people with (pwCF) and without CF were differentiated into PP cells. To evaluate the impact of CFTR function on pancreatic differentiation, protein and transcriptomic analyses, along with immunofluorescence staining, were performed at multiple stages of differentiation under baseline conditions and in the presence of CFTR inhibitors and modulators. We found the differentiation efficiency in iPSC from pwCF to be significantly lower than the control iPSC with some variability depending on the specific CFTR mutation: homozygous ΔF508, nonsense and CFTR 3849+10 kb C→T splicing mutant iPSC were compared. At the PP stage, CF-PP cells exhibited significantly reduced NKX6.1 transcript in comparison to WT-PP cells, supporting a reduced efficiency in early pancreatic development. Pharmacological inhibition of CFTR in WT cells led to a marked decrease in NKX6.1 and PDX1 protein, mirroring the phenotype observed in CF-PP cells along with an increase in differentiation efficiency observed in the presence of CFTR modulators. Our findings demonstrate that CF-PP cells exhibit impaired differentiation efficiency from the primitive gut tube stage of differentiation, a defect recapitulated by pharmacologic CFTR inhibition in non-CF iPSCs. These results support a previously unrecognized role of CFTR in pancreatic development, requiring further investigation of the cellular mechanisms impacted by attenuated CFTR expression/function. The data highlight the need to consider early intervention to restore complete pancreatic function in CF. This study was funded by: University of Iowa Precision Medicine Center for Cystic Fibrosis, funded by the NIH-NIDDK P30 DK054759-22, Cystic Fibrosis Foundation RYAN25I0 and the University of Iowa Stead Family Scholarship all awarded to ALR. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
King et al. (Fri,) studied this question.