Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling
Author
Hohwieler, Meike; Illing, Anett; Hermann, Patrick C.; Mayer, Tobias; Stockmann, Marianne; Perkhofer, Lukas; Eiseler, Tim; Antony, Justin S.; Müller, Martin; Renz, Susanne; Kuo, Chao Chung; Lin, Qiong; Sendler, Matthias; Breunig, Markus; Kleiderman, Susanne M.; Lechel, André; Zenker, Martin; Leichsenring, Michael; Rosendahl, Jonas; Zenke, Martin; Sainz, Bruno; Mayerle, Julia; Costa, Ivan G.; Seufferlein, Thomas; Kormann, Michael; Wagner, Martin; Liebau, Stefan; Kleger, AlexanderEntity
UAM. Departamento de Bioquímica; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)Publisher
BMJ Publishing GroupDate
2017-03-01Citation
10.1136/gutjnl-2016-312423
Gut 66.3 (2016): 473-486
ISSN
0017-5749 (print); 1468-3288 (online)DOI
10.1136/gutjnl-2016-312423Funded by
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, GermanyEditor's Version
http://dx.doi.org/10.1136/gutjnl-2016-312423Subjects
Cystic fibrosis; Pancreas; Stem cells; MedicinaRights
© 2016 Hohwieler M, et alEsta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
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.
Files in this item
Google Scholar:Hohwieler, Meike
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Illing, Anett
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Hermann, Patrick C.
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Mayer, Tobias
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Stockmann, Marianne
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Perkhofer, Lukas
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Eiseler, Tim
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Antony, Justin S.
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Müller, Martin
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Renz, Susanne
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Kuo, Chao Chung
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Lin, Qiong
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Sendler, Matthias
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Breunig, Markus
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Kleiderman, Susanne M.
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Lechel, André
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Zenker, Martin
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Leichsenring, Michael
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Rosendahl, Jonas
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Zenke, Martin
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Sainz, Bruno
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Mayerle, Julia
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Costa, Ivan G.
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Seufferlein, Thomas
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Kormann, Michael
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Wagner, Martin
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Liebau, Stefan
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Kleger, Alexander
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