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Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling
  1. Meike Hohwieler1,
  2. Anett Illing1,
  3. Patrick C Hermann1,
  4. Tobias Mayer1,
  5. Marianne Stockmann1,
  6. Lukas Perkhofer1,
  7. Tim Eiseler1,
  8. Justin S Antony2,
  9. Martin Müller1,
  10. Susanne Renz1,
  11. Chao-Chung Kuo3,
  12. Qiong Lin4,
  13. Matthias Sendler5,
  14. Markus Breunig1,
  15. Susanne M Kleiderman1,
  16. André Lechel1,
  17. Martin Zenker6,
  18. Michael Leichsenring7,
  19. Jonas Rosendahl8,
  20. Martin Zenke4,
  21. Bruno Sainz Jr9,
  22. Julia Mayerle5,
  23. Ivan G Costa3,
  24. Thomas Seufferlein1,
  25. Michael Kormann2,
  26. Martin Wagner1,
  27. Stefan Liebau10,
  28. Alexander Kleger1
  1. 1Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany
  2. 2Department of Pediatrics I, Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy in Pediatrics, University of Tuebingen, Tuebingen, Germany
  3. 3Medical Faculty, IZKF Computational Biology Research Group, RWTH Aachen University, Aachen, Germany
  4. 4Medical Faculty, Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
  5. 5Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany
  6. 6Institute of Human Genetics, University Hospital, Magdeburg, Germany
  7. 7Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
  8. 8Department of Internal Medicine I, Division of Medicine, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
  9. 9Department of Biochemistry, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM, Madrid, Spain
  10. 10Institute of Neuroanatomy, Eberhard Karls University Tuebingen, Tuebingen, Germany
  1. Correspondence to Prof Dr Alexander Kleger, Department of Internal Medicine I, University Medical Center Ulm, Albert-Einstein-Allee 23, Ulm 89081, Germany; alexander.kleger{at}uni-ulm.de

Abstract

Objective 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.

Design We designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny.

Results 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.

Conclusions Taken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures.

  • PANCREAS
  • CYSTIC FIBROSIS
  • STEM CELLS

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • SL and AK jointly supervised this work and contributed equally.

  • Correction notice This article has been corrected since it published Online First. The funding section has been updated.

  • Contributors SL and AK contributed equally to this article. Study concept and design: AK, AI and SL. Acquisition of data: JSA, PCH, BS, MW, AL, JM, MS, C-CK, IGC, LP, MB, MH, TM, MS, SR, MZenker, ML, MM and JR. Analysis and interpretation of data: MH, MW, MK, SL, AK, AI and LP. Drafting of the manuscript: AK, AI, MH and SL. Critical revision of the manuscript for important intellectual content: MZenke, MH, AK, AI, TS, SL and MW. Study supervision: AK, AI and SL.

  • Funding This study was funded by the Deutsche Forschungsgemeinschaft (DFG, K.L. 2544/1-1 and 1-2), the Forschungskern SyStaR to AK, BIU (Böhringer Ingelheim Ulm to AK), the Fritz-Thyssen Foundation (Az. 10.15.2.040), the German Cancer Aid (111879) and the Else-Kröner-Fresenius-Stiftung (2011_A200). AK is indebted to the Baden-Württemberg Stiftung for the financial support of this research project by the Eliteprogramme for Postdocs. AK is also an Else-Kröner-Fresenius Memorial Fellow. LP is supported by a research fellowship of the Else-Kröner-Fresenius-Stiftung. MH was supported by the International Graduate School in Molecular Medicine and the Bausteinprogramme (L.SBN. 110), Ulm University. MM is supported by a grant of Ulm University (Baustein for Senior Clinician Scientists). IGC is funded by the Interdisciplinary Center for Clinical Research (IZKF Aachen) and Start Program, RWTH Aachen University Medical School, Aachen, Germany. AK was supported by an UEG Top Abstract Prize awarded at the United European Gastroenterology Week 2015.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Local ethics committee at Ulm University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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