RT Journal Article
SR Electronic
T1 Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2016-312423
DO 10.1136/gutjnl-2016-312423
A1 Meike Hohwieler
A1 Anett Illing
A1 Patrick C Hermann
A1 Tobias Mayer
A1 Marianne Stockmann
A1 Lukas Perkhofer
A1 Tim Eiseler
A1 Justin S Antony
A1 Martin Müller
A1 Susanne Renz
A1 Chao-Chung Kuo
A1 Qiong Lin
A1 Matthias Sendler
A1 Markus Breunig
A1 Susanne M Kleiderman
A1 André Lechel
A1 Martin Zenker
A1 Michael Leichsenring
A1 Jonas Rosendahl
A1 Martin Zenke
A1 Bruno Sainz, Jr
A1 Julia Mayerle
A1 Ivan G Costa
A1 Thomas Seufferlein
A1 Michael Kormann
A1 Martin Wagner
A1 Stefan Liebau
A1 Alexander Kleger
YR 2016
UL http://gut.bmj.com/content/early/2016/09/15/gutjnl-2016-312423.abstract
AB 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.