title: Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling.
abstract: The generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment.
  
  
  
  We designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny.
  
  
  
  Extensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro,but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids.
  
  
  
  Taken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures.
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Hohwieler
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Illing
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Hermann
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Mayer
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Stockmann
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Perkhofer
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Eiseler
authors.affiliation: Department of Pediatrics I, Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy in Pediatrics, University of Tuebingen, Tuebingen, Germany.
authors.forename: Justin S
authors.initials: JS
authors.lastname: Antony
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Renz
authors.affiliation: Medical Faculty, IZKF Computational Biology Research Group, RWTH Aachen University, Aachen, Germany.
authors.forename: Chao-Chung
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Medical Faculty, Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Breunig
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Kleiderman
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.affiliation: Institute of Human Genetics, University Hospital, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Leichsenring
authors.affiliation: Department of Internal Medicine I, Division of Medicine, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Rosendahl
authors.affiliation: Medical Faculty, Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenke
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sainz
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: Medical Faculty, IZKF Computational Biology Research Group, RWTH Aachen University, Aachen, Germany.
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Costa
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.affiliation: Department of Pediatrics I, Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy in Pediatrics, University of Tuebingen, Tuebingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kormann
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University Tuebingen, Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.affiliation: Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleger
mesh_terms: D061354:Acinar Cells / Q000166:cytology; D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D009940:Organoids / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism / Q000637:transplantation*; D010179:Pancreas / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology; D010641:Phenotype; D039904:Pluripotent Stem Cells; D012333:RNA, Messenger / Q000627:therapeutic use*
chemical_list: D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CYSTIC FIBROSIS; PANCREAS; STEM CELLS