Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids.,Nature Medicine

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Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids.
Nature Medicine ( IF 82.9 ) Pub Date : 2017-Aug-01 , DOI: 10.1038/nm.4360
Fotios Sampaziotis _{1,

2,

3} , Alexander W Justin ₄ , Olivia C Tysoe _{1,

2} , Stephen Sawiak ₅ , Edmund M Godfrey ₆ , Sara S Upponi ₆ , Richard L Gieseck ₇ , Miguel Cardoso de Brito _{1,

2} , Natalie Lie Berntsen ₈ , María J Gómez-Vázquez ₉ , Daniel Ortmann _{1,

2} , Loukia Yiangou _{1,

10,

11} , Alexander Ross _{1,

12,

13} , Johannes Bargehr _{1,

10,

11,

11} , Alessandro Bertero _{1,

2} , Mariëlle C F Zonneveld ₁ , Marianne T Pedersen ₁₄ , Matthias Pawlowski ₁ , Laura Valestrand ₈ , Pedro Madrigal _{1,

15} , Nikitas Georgakopoulos ₂ , Negar Pirmadjid ₂ , Gregor M Skeldon _{16,

17} , John Casey ₁₈ , Wenmiao Shu _{16,

17} , Paulina M Materek ₁₉ , Kirsten E Snijders ₁ , Stephanie E Brown _{1,

2} , Casey A Rimland _{1,

2,

7,

20} , Ingrid Simonic ₂₁ , Susan E Davies ₂₂ , Kim B Jensen ₁₃ , Matthias Zilbauer _{1,

11} , William T H Gelson ₃ , Graeme J Alexander _{10,

11} , Sanjay Sinha _{1,

12} , Nicholas R F Hannan _{23,

24} , Thomas A Wynn ₇ , Tom H Karlsen ₈ , Espen Melum ₈ , Athina E Markaki ₄ , Kourosh Saeb-Parsy ₂ , Ludovic Vallier _{1,

2,

15}

Affiliation

Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK.
Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Department of Engineering, University of Cambridge, Cambridge, UK.
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Cambridge Genomic Services, Department of Pathology, University of Cambridge, Cambridge, UK.
Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
University Department of Paediatrics, University of Cambridge, Cambridge, UK.
Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Wellcome Trust Sanger Institute, Hinxton, UK.
School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK.
Department of Biomedical Engineering, University of Strathclyde, Glasgow, UK.
Department of Surgery, University of Edinburgh, Edinburgh Royal Infirmary, Edinburgh, UK.
NIHR Cambridge Biomedical Centre (BRC) hIPSCs Core Facility, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
University of North Carolina, Chapel Hill, School of Medicine, Chapel Hill, North Carolina, USA.
Medical Genetics Laboratories, Cambridge University Hospitals NHS Trust, Cambridge, UK.
Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Center for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct-like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro.

中文翻译：

使用原代人肝外胆管细胞类器官重建小鼠肝外胆管树。

胆总管 (CBD) 疾病（如胆道闭锁或缺血性狭窄）的治疗受到缺乏适合手术重建的健康供体胆道组织的限制。在这里，我们报告了一种以肝外胆管细胞类器官 (ECO) 的形式从肝外胆管树分离和繁殖人胆管细胞的新方法，用于再生医学应用。由此产生的 ECO 在转录组学特征和功能特性方面与原代胆管细胞非常相似。我们探索了这些类器官在体内的再生潜力，并证明在免疫功能低下小鼠的肾囊下移植后，ECO 自组织成胆管样管，表达胆道标志物。此外，当播种在可生物降解的支架上时，ECO 形成保留胆道特征的组织样结构。由此产生的生物工程组织可以重建胆囊壁并在移植到小鼠损伤模型后修复胆道上皮细胞。此外，生物工程人造导管可以替代天然 CBD，没有胆汁淤积或管腔闭塞的证据。总之，ECO 可以成功重建胆道树，为使用体外扩增的人原代胆管细胞进行器官再生提供了原理证明。没有胆汁淤积或管腔闭塞的证据。总之，ECO 可以成功重建胆道树，为使用体外扩增的人原代胆管细胞进行器官再生提供了原理证明。没有胆汁淤积或管腔闭塞的证据。总之，ECO 可以成功重建胆道树，为使用体外扩增的人原代胆管细胞进行器官再生提供了原理证明。

更新日期：2017-09-07

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