TY - JOUR T1 - Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling JF - Gut JO - Gut DO - 10.1136/gutjnl-2016-312423 SP - gutjnl-2016-312423 AU - Meike Hohwieler AU - Anett Illing AU - Patrick C Hermann AU - Tobias Mayer AU - Marianne Stockmann AU - Lukas Perkhofer AU - Tim Eiseler AU - Justin S Antony AU - Martin Müller AU - Susanne Renz AU - Chao-Chung Kuo AU - Qiong Lin AU - Matthias Sendler AU - Markus Breunig AU - Susanne M Kleiderman AU - André Lechel AU - Martin Zenker AU - Michael Leichsenring AU - Jonas Rosendahl AU - Martin Zenke AU - Bruno Sainz, Jr AU - Julia Mayerle AU - Ivan G Costa AU - Thomas Seufferlein AU - Michael Kormann AU - Martin Wagner AU - Stefan Liebau AU - Alexander Kleger Y1 - 2016/09/15 UR - http://gut.bmj.com/content/early/2016/09/15/gutjnl-2016-312423.abstract N2 - 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. ER -