title: GATA6 Plays an Important Role in the Induction of Human Definitive Endoderm, Development of the Pancreas, and Functionality of Pancreatic β Cells.
abstract: Induced pluripotent stem cells were created from a pancreas agenesis patient with a mutation in GATA6. Using genome-editing technology, additional stem cell lines with mutations in both GATA6 alleles were generated and demonstrated a severe block in definitive endoderm induction, which could be rescued by re-expression of several different GATA family members. Using the endodermal progenitor stem cell culture system to bypass the developmental block at the endoderm stage, cell lines with mutations in one or both GATA6 alleles could be differentiated into β-like cells but with reduced efficiency. Use of suboptimal doses of retinoic acid during pancreas specification revealed a more severe phenotype, more closely mimicking the patient's disease. GATA6 mutant β-like cells fail to secrete insulin upon glucose stimulation and demonstrate defective insulin processing. These data show that GATA6 plays a critical role in endoderm and pancreas specification and β-like cell functionality in humans.
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Tiyaboonchai
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Fabian L
authors.initials: FL
authors.lastname: Cardenas-Diaz
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Ying
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Jean Ann
authors.initials: JA
authors.lastname: Maguire
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Graduate Program in Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Sim
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Chintan
authors.initials: C
authors.lastname: Jobaliya
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Alyssa L
authors.initials: AL
authors.lastname: Gagne
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Graduate Program in Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Kishore
authors.affiliation: Division of Endocrinology, Department of Pediatrics, Perelman School of Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Diana E
authors.initials: DE
authors.lastname: Stanescu
authors.affiliation: Clinical and Translational Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Nkecha
authors.initials: N
authors.lastname: Hughes
authors.affiliation: Division of Endocrinology, Department of Pediatrics, Perelman School of Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Diva D
authors.initials: DD
authors.lastname: De Leon
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: French
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, CTRB 5012, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: gaduep@email.chop.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Gadue
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004707:Endoderm / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D050993:GATA6 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008954:Models, Biological; D005810:Multigene Family; D009154:Mutation; D010179:Pancreas / Q000196:embryology / Q000378:metabolism*; D010641:Phenotype; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D050993:GATA6 Transcription Factor; D036341:Intercellular Signaling Peptides and Proteins; D014212:Tretinoin
keywords: GATA6; definitive endoderm; pancreatic agenesis; retinoic acid; stem cells; β cell