title: Modeling Cystic Fibrosis Using Pluripotent Stem Cell-Derived Human Pancreatic Ductal Epithelial Cells.
abstract: We established an efficient strategy to direct human pluripotent stem cells, including human embryonic stem cells (hESCs) and an induced pluripotent stem cell (iPSC) line derived from patients with cystic fibrosis, to differentiate into pancreatic ductal epithelial cells (PDECs). After purification, more than 98% of hESC-derived PDECs expressed functional cystic fibrosis transmembrane conductance regulator (CFTR) protein. In addition, iPSC lines were derived from a patient with CF carrying compound frameshift and mRNA splicing mutations and were differentiated to PDECs. PDECs derived from Weill Cornell cystic fibrosis (WCCF)-iPSCs showed defective expression of mature CFTR protein and impaired chloride ion channel activity, recapitulating functional defects of patients with CF at the cellular level. These studies provide a new methodology to derive pure PDECs expressing CFTR and establish a "disease in a dish" platform to identify drug candidates to rescue the pancreatic defects of patients with CF.
  
  
  CONCLUSIONS
  An efficient strategy was established to direct human pluripotent stem cells, including human embryonic stem cells (hESCs) and an induced pluripotent stem cell line derived from patients with cystic fibrosis (CF-iPSCs), to differentiate into pancreatic ductal epithelial cells (PDECs). After purification, more than 98% of hESC-PDECs derived from CF-iPSCs showed defective expression of mature cystic fibrosis transmembrane conductance regulator (CFTR) protein and impaired chloride ion channel activity, recapitulating functional pancreatic defects of patients with CF at the cellular level. These studies provide a new methodology for deriving pure PDECs expressing CFTR, and they establish a "disease-in-a-dish" platform for identifying drug candidates to rescue the pancreatic defects of these patients.
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Senem
authors.initials: S
authors.lastname: Simsek
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Robinson
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Su-Yi
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Crespo
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Amin
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Hon
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Evans
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York, USADepartment of Biochemistry, Weill Cornell Medical College, New York, New York, USA shc2034@med.cornell.edu.
authors.forename: Shuibing
authors.initials: S
authors.lastname: Chen
mesh_terms: D015374:Biosensing Techniques; D002454:Cell Differentiation; D002460:Cell Line; D002469:Cell Separation / Q000379:methods; D018920:Coculture Techniques; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D016368:Frameshift Mutation; D005786:Gene Expression Regulation; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D010183:Pancreatic Ducts / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012326:RNA Splicing; D013997:Time Factors; D014162:Transfection
chemical_list: C505032:CFTR protein, human; D005819:Genetic Markers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: Chloride ion efflux assay; Directed differentiation; Pancreatic defects of cystic fibrosis; Reprogramming