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1. Single-cell atlas of human liver development reveals pathways directing hepatic cell fates

Author

Brandon T. Wesley, Alexander D. B. Ross, Daniele Muraro, Zhichao Miao, Sarah Saxton, Rute A. Tomaz, Carola M. Morell, Katherine Ridley, Ekaterini D. Zacharis, Sandra Petrus-Reurer, Judith Kraiczy, Krishnaa T. Mahbubani, Stephanie Brown, Jose Garcia-Bernardo, Clara Alsinet, Daniel Gaffney, Dave Horsfall, Olivia C. Tysoe, Rachel A. Botting, Emily Stephenson, Dorin-Mirel Popescu, Sonya MacParland, Gary Bader, Ian D. McGilvray, Daniel Ortmann, Fotios Sampaziotis, Kourosh Saeb-Parsy, Muzlifah Haniffa, Kelly R. Stevens, Matthias Zilbauer, Sarah A. Teichmann, and Ludovic Vallier

Subjects
Organoids, Liver, Hepatocytes, Humans, Cell Differentiation, Cell Biology, Transcription Factors
Abstract

The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications.

Published
2022

2. Organoids and regenerative hepatology

Author

Nidhi Jalan‐Sakrikar, Teresa Brevini, Robert C. Huebert, Fotios Sampaziotis, Huebert, Robert C [0000-0002-9812-7573], and Apollo - University of Cambridge Repository

Subjects
Organoids, Hepatology, Liver, Gastroenterology, Hepatocytes, Humans, Regenerative Medicine, Article
Abstract

The burden of liver diseases is increasing worldwide, with liver transplantation remaining the only treatment option for end-stage liver disease. Regenerative medicine holds great potential as a therapeutic alternative, aiming to repair or replace damaged liver tissue with healthy functional cells. The properties of the cells used are critical for the efficacy of this approach. The advent of liver organoids has not only offered new insights into human physiology and pathophysiology, but also provided an optimal source of cells for regenerative medicine and translational applications. Here, we discuss various historical aspects of 3D organoid culture, how it has been applied to the hepatobiliary system, and how organoid technology intersects with the emerging global field of liver regenerative medicine. We outline the hepatocyte, cholangiocyte, and nonparenchymal organoids systems available and discuss their advantages and limitations for regenerative medicine as well as future directions.

Published
2022

3. Tissue engineering of the biliary tract and modelling of cholestatic disorders

Author

Teresa Brevini, Olivia C. Tysoe, and Fotios Sampaziotis

Subjects
0301 basic medicine, Cholestasis, Tissue Engineering, Hepatology, business.industry, Epithelial Cells, Disease pathogenesis, Dynamic modelling, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Tissue engineering, Biliary tract, Animals, Humans, Medicine, 030211 gastroenterology & hepatology, Cholestatic liver disease, Biliary Tract, business, Neuroscience
Abstract

Summary Our insight into the pathogenesis of cholestatic liver disease remains limited, partly owing to challenges in capturing the multitude of factors that contribute to disease pathogenesis in vitro. Tissue engineering could address this challenge by combining cells, materials and fabrication strategies into dynamic modelling platforms, recapitulating the multifaceted aetiology of cholangiopathies. Herein, we review the advantages and limitations of platforms for bioengineering the biliary tree, looking at how these can be applied to model biliary disorders, as well as exploring future directions for the field.

Published
2020

4. What gastroenterologists and hepatologists should know about organoids in 2019

Author

Markus F. Neurath, Fotios Sampaziotis, Claudia Günther, and Teresa Brevini

Subjects
0301 basic medicine, Induced Pluripotent Stem Cells, Computational biology, Regenerative Medicine, Models, Biological, Regenerative medicine, Translational Research, Biomedical, 03 medical and health sciences, 0302 clinical medicine, Tissue engineering, Organoid, Animals, Humans, Medicine, Disease, Precision Medicine, Induced pluripotent stem cell, Hepatology, business.industry, Gastroenterology, Organoids, 030104 developmental biology, Organ Specificity, Cancer cell, 030211 gastroenterology & hepatology, Personalized medicine, business, Stem cell biology, In vitro cell culture
Abstract

Most of the research behind new medical advances is carried out using either animal models or cancer cells, which both have their disadvantage in particular with regard to medical applications such as personalized medicine and novel therapeutic approaches. However, recent advances in stem cell biology have enabled long-term culturing of organotypic intestinal or hepatic tissues derived from tissue resident or pluripotent stem cells. These 3D structures, denoted as organoids, represent a substantial advance in structural and functional complexity over traditional in vitro cell culture models that are often non-physiological and transformed. They can recapitulate the in vivo architecture, functionality and genetic signature of the corresponding tissue. The opportunity to model epithelial cell biology, epithelial turnover, barrier dynamics, immune-epithelial communication and host-microbe interaction more efficiently than previous culture systems, greatly enhance the translational potential of organotypic hepato-gastrointestinal culture systems. Thus there is increasing interest in using such cultured cells as a source for tissue engineering, regenerative medicine and personalized medicine. This review will highlight some of the established and also some exciting novel perspectives on organoids in the fields of gastroenterology and hepatology.

Published
2019

5. Regional differences in human biliary tissues and corresponding in vitro derived organoids

Author

Matthias Zilbauer, Olivia C. Tysoe, Daniele Muraro, Ludovic Vallier, Carola M. Morell, Nicholas R.F. Hannan, Stuart J. Forbes, Samantha G. Tilson, Richard L. Gieseck, Thomas A. Wynn, Simone E. Adams, Rute A. Tomaz, Brandon T Wesley, Wei-Yu Lu, Judith Kraiczy, John R. Ferdinand, Kourosh Saeb-Parsy, Gabriel C. Oniscu, Alexander Ross, Casey A. Rimland, Francisco Otaizo-Carrasquero, Nikitas Georgakopoulos, Timothy G. Myers, and Fotios Sampaziotis

Subjects
0301 basic medicine, Tissue and Organ Procurement, Cellular differentiation, Intrahepatic bile ducts, Biology, Cholangiocyte, 03 medical and health sciences, Mice, 0302 clinical medicine, Liver Injury and Regeneration, Bile Ducts, Extrahepatic, Organoid, medicine, Animals, Bile, Humans, RNA-Seq, Pancreatic duct, Common Bile Duct, Keratin-19, Common bile duct, Hepatology, Gallbladder, Wnt signaling pathway, Cell Differentiation, Epithelial Cells, Original Articles, Cell biology, Organoids, 030104 developmental biology, medicine.anatomical_structure, Bile Ducts, Intrahepatic, Gene Expression Regulation, Liver, 030211 gastroenterology & hepatology, Original Article
Abstract

Background and aims Organoids provide a powerful system to study epithelia in vitro. Recently, this approach was applied successfully to the biliary tree, a series of ductular tissues responsible for the drainage of bile and pancreatic secretions. More precisely, organoids have been derived from ductal tissue located outside (extrahepatic bile ducts; EHBDs) or inside the liver (intrahepatic bile ducts; IHBDs). These organoids share many characteristics, including expression of cholangiocyte markers such as keratin (KRT) 19. However, the relationship between these organoids and their tissues of origin, and to each other, is largely unknown. Approach and results Organoids were derived from human gallbladder, common bile duct, pancreatic duct, and IHBDs using culture conditions promoting WNT signaling. The resulting IHBD and EHBD organoids expressed stem/progenitor markers leucine-rich repeat-containing G-protein-coupled receptor 5/prominin 1 and ductal markers KRT19/KRT7. However, RNA sequencing revealed that organoids conserve only a limited number of regional-specific markers corresponding to their location of origin. Of particular interest, down-regulation of biliary markers and up-regulation of cell-cycle genes were observed in organoids. IHBD and EHBD organoids diverged in their response to WNT signaling, and only IHBDs were able to express a low level of hepatocyte markers under differentiation conditions. Conclusions Taken together, our results demonstrate that differences exist not only between extrahepatic biliary organoids and their tissue of origin, but also between IHBD and EHBD organoids. This information may help to understand the tissue specificity of cholangiopathies and also to identify targets for therapeutic development.

Published
2020
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6. Advances in the generation of bioengineered bile ducts

Author

Athina E. Markaki, Fotios Sampaziotis, Kourosh Saeb-Parsy, Alexander W. Justin, Ludovic Vallier, Saeb-Parsy, Kourosh [0000-0002-0633-3696], Markaki, Athina [0000-0002-2265-1256], Vallier, Ludovic [0000-0002-3848-2602], Sampaziotis, Fotios [0000-0003-0812-7586], and Apollo - University of Cambridge Repository

Subjects
Cholangiopathy, 0301 basic medicine, Pathology, medicine.medical_specialty, medicine.medical_treatment, Biomedical Engineering, Cell Culture Techniques, Bioengineering, Bile Duct Diseases, Liver transplantation, Bioinformatics, Cholangiocyte, 03 medical and health sciences, Organ Culture Techniques, Tissue engineering, Biliary atresia, Animals, Humans, Medicine, Molecular Biology, Bioartificial Organs, Tissue Engineering, business.industry, Bile duct, Epithelial Cells, medicine.disease, Coculture Techniques, Liver Transplantation, 3. Good health, Transplantation, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cell culture, Molecular Medicine, Bile Ducts, business
Abstract

The generation of bioengineered biliary tissue could contribute to the management of some of the most impactful cholangiopathies associated with liver transplantation, such as biliary atresia or ischemic cholangiopathy. Recent advances in tissue engineering and in vitro cholangiocyte culture have made the achievement of this goal possible. Here we provide an overview of these developments and review the progress towards the generation and transplantation of bioengineered bile ducts. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.

Published
2018

7. Directed differentiation of human induced pluripotent stem cells into functional cholangiocyte-like cells

Author

Nicholas R.F. Hannan, Alessandro Bertero, Fotios Sampaziotis, Ludovic Vallier, Miguel Cardoso de Brito, Imbisaat Geti, Sampaziotis, Fotios [0000-0003-0812-7586], Vallier, Ludovic [0000-0002-3848-2602], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cellular differentiation, Induced Pluripotent Stem Cells, Cell Culture Techniques, Stem-cell differentiation, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Cholangiocyte, 03 medical and health sciences, Directed differentiation, Pluripotent stem cells, medicine, Humans, Progenitor cell, Induced pluripotent stem cell, Disease model, Cell Differentiation, Epithelial Cells, Cell biology, Endothelial stem cell, 030104 developmental biology, medicine.anatomical_structure, Immunology, Cell culture, Bile Ducts, Stem cell, Endoderm
Abstract

The difficulty in isolating and propagating functional primary cholangiocytes is a major limitation in the study of biliary disorders and the testing of novel therapeutic agents. To overcome this problem, we have developed a platform for the differentiation of human pluripotent stem cells (hPSCs) into functional cholangiocyte-like cells (CLCs). We have previously reported that our 26-d protocol closely recapitulates key stages of biliary development, starting with the differentiation of hPSCs into endoderm and subsequently into foregut progenitor (FP) cells, followed by the generation of hepatoblasts (HBs), cholangiocyte progenitors (CPs) expressing early biliary markers and mature CLCs displaying cholangiocyte functionality. Compared with alternative protocols for biliary differentiation of hPSCs, our system does not require coculture with other cell types and relies on chemically defined conditions up to and including the generation of CPs. A complex extracellular matrix is used for the maturation of CLCs; therefore, experience in hPSC culture and 3D organoid systems may be necessary for optimal results. Finally, the capacity of our platform for generating large amounts of disease-specific functional cholangiocytes will have broad applications for cholangiopathies, in disease modeling and for screening of therapeutic compounds.

Published
2017

8. Cholangiocyte organoids can repair bile ducts after transplantation in the human liver

Author

Sanjay Sinha, Victoria L. Mulcahy, William Gelson, Kourosh Saeb-Parsy, Brandon T Wesley, Sarah A. Teichmann, Laure Gambardella, Timothy E. Beach, Sharayne Robinson, Michael P. Murphy, Paul Gibbs, Stephanie Brown, Richard L. Gieseck, Peter C. Humphreys, Corrina Fear, Anna Osnato, Krishnaa T. Mahbubani, Gareth Corbett, Irum Amin, Olivia C. Tysoe, Daniele Muraro, Christopher J.E. Watson, Espen Melum, Daniel Ortmann, Andrew J. Butler, George F. Mells, Teresa Brevini, Keziah Crick, Sara Upponi, Fotios Sampaziotis, Susan E. Davies, Teik Choon See, Giovanni Canu, Stephen J. Sawiak, Jose Garcia-Bernardo, Edmund Godfrey, Ludovic Vallier, N.L. Berntsen, Lisa Swift, Johannes Bargehr, Sampaziotis, Fotios [0000-0003-0812-7586], Muraro, Daniele [0000-0001-9601-237X], Tysoe, Olivia C [0000-0002-1061-1484], Sawiak, Stephen [0000-0003-4210-9816], Brevini, Teresa [0000-0002-3581-5379], Wesley, Brandon T [0000-0003-0530-329X], Garcia-Bernardo, Jose [0000-0003-3626-5433], Mahbubani, Krishnaa [0000-0002-1327-2334], Canu, Giovanni [0000-0002-3349-4479], Berntsen, Natalie L [0000-0002-5949-8910], Mulcahy, Victoria L [0000-0001-7091-4789], Robinson, Sharayne [0000-0001-6819-3433], Swift, Lisa [0000-0001-9044-688X], Gambardella, Laure [0000-0001-5771-1565], Bargehr, Johannes [0000-0002-9304-3573], Osnato, Anna [0000-0001-5241-1512], Murphy, Michael P [0000-0003-1115-9618], Gibbs, Paul [0000-0003-2193-5377], Sinha, Sanjay [0000-0001-5900-1209], Teichmann, Sarah A [0000-0002-6294-6366], Melum, Espen [0000-0001-6903-6878], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Vallier, Ludovic [0000-0002-3848-2602], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Tissue and Organ Procurement, medicine.medical_treatment, Cell- and Tissue-Based Therapy, Context (language use), Bile Duct Diseases, Biology, Liver transplantation, Mesenchymal Stem Cell Transplantation, Regenerative medicine, Cholangiocyte, 03 medical and health sciences, Mice, 0302 clinical medicine, In vivo, Organoid, medicine, Animals, Bile, Humans, RNA-Seq, Common Bile Duct, Multidisciplinary, Gallbladder, Epithelial Cells, Cell biology, Liver Transplantation, Transplantation, Organoids, 030104 developmental biology, Bile Ducts, Intrahepatic, Gene Expression Regulation, Liver, 030211 gastroenterology & hepatology, Bile Ducts, Transcriptome, Ex vivo
Abstract

Organoids regenerate human bile ducts Bile ducts carry bile from the liver and gall bladder to the small intestine, where it aids digestion. Cholangiocytes are epithelial cells that line bile ducts and modify bile as its transported through the biliary tree. Chronic liver diseases involving cholangiocytes account for a large fraction of liver failure and the need for liver transplantation. Because liver donors are in short supply, Sampaziotis et al. used organoid technology to develop a cell-based therapy using human tissue (see the Perspective by Kurial and Willenbring). Cholangiocyte organoids were transplanted into the intrahepatic ducts of deceased human donor livers undergoing ex vivo normothermic perfusion. The livers could be maintained for up to 100 hours, and the transplanted organoids engrafted, exhibited function, and could repair bile ducts. Science , this issue p. 839 ; see also p. 786

Published
2019

9. Epicardial cells derived from human embryonic stem cells augment cardiomyocyte-driven heart regeneration

Author

William G. Bernard, Nichola Figg, Amy M. Martinson, Laure Gambardella, Shiv Bhandari, Dharini Iyer, Hongorzul Davaapil, Johannes Bargehr, Michael Regnier, Sanjay Sinha, Nicolas Le Novère, Andrea Leonard, Charles E. Murry, Peter Hofsteen, Fotios Sampaziotis, Alessandro Bertero, Florian Weinberger, Maria Colzani, Martin R. Bennett, L. Ong, Bargehr, Johannes [0000-0002-9304-3573], Ong, Lay Ping [0000-0001-7421-5117], Bertero, Alessandro [0000-0002-4919-9087], Murry, Charles E [0000-0003-3862-6773], Sinha, Sanjay [0000-0001-5900-1209], and Apollo - University of Cambridge Repository

Subjects
Male, Cellular differentiation, Nude, Human Embryonic Stem Cells, Myocardial Infarction, Chick Embryo, Applied Microbiology and Biotechnology, Cell therapy, Rats, Sprague-Dawley, 0302 clinical medicine, Tissue engineering, Medicine, Myocyte, Myocytes, Cardiac, 0303 health sciences, cardiac regeneration, Heart, Epicardium, 3. Good health, Cell biology, surgical procedures, operative, cardiovascular system, Animals, Gene Expression Regulation, Humans, Rats, Rats, Nude, Tissue Engineering, Regeneration, Molecular Medicine, Cardiac, Biotechnology, Biomedical Engineering, regenerative medicine, Bioengineering, Article, Contractility, 03 medical and health sciences, embryonic origin, cell transplantation, 030304 developmental biology, Myocytes, business.industry, Regeneration (biology), Mesenchymal stem cell, epicardial, Embryonic stem cell, Sprague-Dawley, business, 030217 neurology & neurosurgery
Abstract

The epicardium and its derivatives provide trophic and structural support for the developing and adult heart. Here we tested the ability of human embryonic stem cell (hESC)-derived epicardium to augment the structure and function of engineered heart tissue in vitro and to improve efficacy of hESC-cardiomyocyte grafts in infarcted athymic rat hearts. Epicardial cells markedly enhanced the contractility, myofibril structure and calcium handling of human engineered heart tissues, while reducing passive stiffness compared with mesenchymal stromal cells. Transplanted epicardial cells formed persistent fibroblast grafts in infarcted hearts. Cotransplantation of hESC-derived epicardial cells and cardiomyocytes doubled graft cardiomyocyte proliferation rates in vivo, resulting in 2.6-fold greater cardiac graft size and simultaneously augmenting graft and host vascularization. Notably, cotransplantation improved systolic function compared with hearts receiving either cardiomyocytes alone, epicardial cells alone or vehicle. The ability of epicardial cells to enhance cardiac graft size and function makes them a promising adjuvant therapeutic for cardiac repair. Cell therapy in a rat model of heart attack is enhanced by stem-cell-derived epicardium.

Published
2019

10. Isolation and propagation of primary human cholangiocyte organoids for the generation of bioengineered biliary tissue

Author

Ludovic Vallier, Krishnaa T. Mahbubani, Espen Melum, Alexander W. Justin, Si Emma Chen, Olivia C. Tysoe, Hajer Zedira, Teresa Brevini, Athina E. Markaki, Anna Katharina Frank, Kourosh Saeb-Parsy, Fotios Sampaziotis, Frank, Anna K [0000-0003-1378-5129], Sampaziotis, Fotios [0000-0003-0812-7586], and Apollo - University of Cambridge Repository

Subjects
medicine.medical_treatment, Biocompatible Materials, Cell Separation, Biology, Liver transplantation, Regenerative medicine, General Biochemistry, Genetics and Molecular Biology, Cholangiocyte, 03 medical and health sciences, Mice, 0302 clinical medicine, Tissue engineering, Organoid, medicine, Animals, Humans, Regeneration, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Tissue Engineering, Tissue Scaffolds, Regeneration (biology), Equipment Design, 3. Good health, Cell biology, Transplantation, Organoids, Bile Ducts, 030217 neurology & neurosurgery, Adult stem cell
Abstract

Pediatric liver transplantation is often required as a consequence of biliary disorders because of the lack of alternative treatments for repairing or replacing damaged bile ducts. To address the lack of availability of pediatric livers suitable for transplantation, we developed a protocol for generating bioengineered biliary tissue suitable for biliary reconstruction. Our platform allows the derivation of cholangiocyte organoids (COs) expressing key biliary markers and retaining functions of primary extra- or intrahepatic duct cholangiocytes within 2 weeks of isolation. COs are subsequently seeded on polyglycolic acid (PGA) scaffolds or densified collagen constructs for 4 weeks to generate bioengineered tissue retaining biliary characteristics. Expertise in organoid culture and tissue engineering is desirable for optimal results. COs correspond to mature functional cholangiocytes, differentiating our method from alternative organoid systems currently available that propagate adult stem cells. Consequently, COs provide a unique platform for studies in biliary physiology and pathophysiology, and the resulting bioengineered tissue has broad applications for regenerative medicine and cholangiopathies.

Published
2019

11. Use of Biliary Organoids in Cholestasis Research

Author

Fotios, Sampaziotis, Olivia, Tysoe, Teresa, Brevini, and Ludovic, Vallier

Subjects
Organoids, Cholestasis, Liver, Induced Pluripotent Stem Cells, Gallbladder, Humans, Bile Ducts
Abstract

Cholangiocytes play a crucial role in the pathophysiology of cholestasis. However, research on human cholangiocytes has been restricted by challenges in long-term propagation and large-scale expansion of primary biliary epithelium. The advent of organoid technology has overcome this limitation allowing long-term culture of a variety of epithelia from multiple organs. Here, we describe two methods for growing human cholangiocytes in organoid format. The first applies to the generation of intrahepatic bile ducts using human induced pluripotent stem cells using a protocol of differentiation that recapitulates physiological bile duct development. The second method allows the propagation of primary biliary epithelium from the extrahepatic ducts or gallbladder. Both protocols result in large numbers of cholangiocyte organoids expressing biliary markers and maintaining key cholangiocyte functions.

Published
2019

12. Isolation and propagation of primary human cholangiocyte organoids for the generation of bioengineered biliary tissue

Author

Olivia C, Tysoe, Alexander W, Justin, Teresa, Brevini, Si Emma, Chen, Krishnaa T, Mahbubani, Anna K, Frank, Hajer, Zedira, Espen, Melum, Kourosh, Saeb-Parsy, Athina E, Markaki, Ludovic, Vallier, and Fotios, Sampaziotis

Subjects
Organoids, Mice, Tissue Engineering, Tissue Scaffolds, Animals, Humans, Regeneration, Biocompatible Materials, Bile Ducts, Cell Separation, Equipment Design, Cells, Cultured
Abstract

Pediatric liver transplantation is often required as a consequence of biliary disorders because of the lack of alternative treatments for repairing or replacing damaged bile ducts. To address the lack of availability of pediatric livers suitable for transplantation, we developed a protocol for generating bioengineered biliary tissue suitable for biliary reconstruction. Our platform allows the derivation of cholangiocyte organoids (COs) expressing key biliary markers and retaining functions of primary extra- or intrahepatic duct cholangiocytes within 2 weeks of isolation. COs are subsequently seeded on polyglycolic acid (PGA) scaffolds or densified collagen constructs for 4 weeks to generate bioengineered tissue retaining biliary characteristics. Expertise in organoid culture and tissue engineering is desirable for optimal results. COs correspond to mature functional cholangiocytes, differentiating our method from alternative organoid systems currently available that propagate adult stem cells. Consequently, COs provide a unique platform for studies in biliary physiology and pathophysiology, and the resulting bioengineered tissue has broad applications for regenerative medicine and cholangiopathies.

Published
2018

13. Building better bile ducts

Author

Fotios Sampaziotis

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Cirrhosis, medicine.medical_treatment, Cell Culture Techniques, Drug Evaluation, Preclinical, Bile Duct Diseases, Liver transplantation, In Vitro Techniques, digestive system, 03 medical and health sciences, Mice, Medicine, Animals, Humans, Multidisciplinary, Tissue Engineering, business.industry, medicine.disease, Organoids, 030104 developmental biology, Bile Ducts, business, Transport system
Abstract

The bile ducts form a network of tubes within the liver and transfer bile produced in the liver to the bowel. In biliary disorders, this transport system fails, leading to the accumulation of toxic bile in the liver, damage, and permanent scarring (cirrhosis), which can ultimately be treated only through liver transplantation. Indeed, bile duct diseases (cholangiopathies) are the leading disorder treated (70%) by pediatric liver transplantation and account for a third of adult transplanted livers.

Published
2018

14. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

Author

Marco Carbone, Alessandra Nardi, Steve Flack, Guido Carpino, Nikoletta Varvaropoulou, Caius Gavrila, Ann Spicer, Jonathan Badrock, Francesca Bernuzzi, Vincenzo Cardinale, Holly F Ainsworth, Michael A Heneghan, Douglas Thorburn, Andrew Bathgate, Rebecca Jones, James M Neuberger, Pier Maria Battezzati, Massimo Zuin, Simon Taylor-Robinson, Maria F Donato, John Kirby, Robert Mitchell-Thain, Annarosa Floreani, Fotios Sampaziotis, Luigi Muratori, Domenico Alvaro, Marco Marzioni, Luca Miele, Fabio Marra, Edoardo Giannini, Eugenio Gaudio, Vincenzo Ronca, Giulia Bonato, Laura Cristoferi, Federica Malinverno, Alessio Gerussi, Deborah D Stocken, Heather J Cordell, Gideon M Hirschfield, Graeme J Alexander, Richard N Sandford, David E Jones, Pietro Invernizzi, George F Mells, Caradog Thomas, Meshbah Rahman, Tom Yapp, Chin Lye Ch'ng, Melanie Harrison, Richard Sturgess, Roman Galaska, Chris Healey, Jessica Whiteman, Marek Czaijkowski, Catherine Gray, Anton Gunasekera, Pranab Gyawli, Purushothaman Premchand, Steven Mann, Keith Elliott, Kapil Kapur, Alan Watson, Graham Foster, Paul Trembling, Javaid Subhani, Rory Harvey, Roger McCorry, Carolyn Adgey, Lucie Hobson, Caroline Mulvaney-Jones, Richard Evans, Thiriloganathan Mathialahan, David Ramanaden, Jaber Gasem, Greta Van Duyvenvoorde, Christopher Shorrock, Katie Seward, Paul Southern, Jeremy Tibble, Ruth Penn, David Gorard, Jane Maiden, Rose Damant, Altaf Palegwala, Susan Jones, Graeme Alexander, George Mells, Richard Sandford, Sunil Dolwani, Martin Prince, Valeria Silvestre, Matthew Foxton, Eleanor Dungca, Harriet Mitchison, Natalie Wheatley, Ian Gooding, Helen Doyle, Mazn Karmo, Melanie Kent, Sushma Saksena, Delyth Braim, Minesh Patel, Susan Lord, Roland Ede, Alison Paton, Andrew Austin, Nicola Lancaster, Joanna Sayer, Andrew Gibbins, Karen Hogben, Chris Hovell, Neil Fisher, Martyn Carter, Konrad Koss, Janine Musselwhite, Florin Muscariu, Andrzej Piotreowicz, Alexandra McKay, Charles Grimley, David Neal, Lai Ting Tan, Guan Lim, Jacqueline Brighton, Carole Foale, Aftab Ala, Athar Saeed, Kerry Flahive, Gordon Wood, Paula Townshend, Chris Ford, Jonathan Brown, Jean Kordula, Jane Bowles, Mark Wilkinson, Caroline Palmer, John Ramage, Harriet Gordon, James Featherstone, Jo Ridpath, Theodore Ngatchu, Sass Levi, Syed Shaukat, Joy Sadeghian, Ray Shidrawi, Bronwen Williams, George Abouda, Sarah Jones, Claire Duggan, Abigail Hynes, Mark Narain, Ian Rees, Imroz Salam, Mary Crossey, Ashley Brown, Carolyn MacNicol, Simon Williams, Elva Wilhelmsen, Paul Banim, Parizade Raymode, Andrew Chilton, Debasish Das, Hye-Jeong Lee, Howard Curtis, Michael Heneghan, Markus Gess, Emma Durant, IM Drake, Rebecca Bishop, Mervyn Davies, Mark Aldersley, Noma Ncube, Alistair McNair, Raj Srirajaskanthan, Sambit Sen, Rebecca Casey, George Bird, Mike Mendall, Caroline Cowley, Adrian Barnardo, Paul Kitchen, Kevin Yoong, Kelly Amore, Dawn Sirdefield, Jacky Orpe, Ray Mathew, George MacFaul, Aruna Wrigth, Amir Shah, Chris Evans, Janie Keggans, Bridget Bird, Gwen Baxter, Subrata Saha, Katharine Pollock, Maggie Hughes, Peter Bramley, Emma Grieve, Karin Young, Andrew Fraser, Ashis Mukhopadhya, Kate Ocker, Peter Mills, Francis Hines, Chris Shallcross, Joy Wilkins, Leonie Grellier, Stewart Campbell, Kirsty Martin, Caron Innes, Alan Shepherd, Simon Rushbrook, Talal Valliani, Robert Przemioslo, Helen Fairlamb, Chris Macdonald, Anne Eastick, Jane Metcalf, Elizabeth Tanqueray, Udi Shmueli, Becky Holbrook, Andrew Davis, Julie Browning, Asifabbas Naqvi, Kirsten Walker, Tom Lee, Juliette Verheyden, Susan Slininger, Stephen D Ryder, Roger Chapman, Jane Collier, Denise O'Donnell, Lizzie Stafford, Kate Williamson, Linda Kent, Howard Klass, Mary Ninkovic, Linda March, Matthew Cramp, Diane Simpson, Christine Dickson, Nicholas Sharer, Maria Hayes, Patrick Goggin, Mary Quinne, Sallyanne Pearson, Barbara Hoeroldt, Linda Jones, Alice Wright, Jonathan Booth, Alison Loftus, George Lipscomb, Hannah Dewhurst, Emma Gunter, Earl Williams, Anna Fouracres, Liz Farrington, Lyn Graves, Hyder Hussaini, Bill Stableforth, Suzie Marriott, Reuben Ayres, Marina Leoni, Andrew Burroughs, Eileen Marshall, David Tyrer, Kate Martin, Martin Lombard, Imran Patanwala, Lola Dali-Kemmery, Victoria Lambourne, Julia Maltby, Samir Vyas, Julie Colley, Bal Shinder, Saket Singhal, Jayne Jones, Marisa Mills, Dermot Gleeson, Mandy Carnahan, Jeff Butterworth, Kerenza Boulton, Natalie Taylor, Keith George, Tim Harding, Julie Tregonning, Andrew Douglass, Carly Brown, Gayle Clifford, Simon Panter, Denise Gocher, Jeremy Shearman, Gary Bray, Maria Hamilton, Graham Butcher, Daniel Forton, John Mclindon, Janette Curtis, Debashis Das, Tracey Shewan, Matthew Cowan, Gregory Whatley, Mariam Nasseri, Bob Grover, Nurani Sivaramakrishnan, Samantha Ducker, Kathryn Houghton, David Jones, Laura Griffiths, Sherill Tripoli, Maxton Pitcher, Ervin Shpuza, Nikki White, Deb Ghosh, Andrew Douds, Marie Green, Matthew Brookes, Lourdes Cumlat, Voi Shim Wong, Karen Warner, Kimberley Netherton, Adtya Mandal, Snjiv Jain, Hemant Gupta, Pradeep Sanghi, Steve Pereira, James Neuberger, Bridget Gunson, Gideon Hirschfield, Reina Teegan Lim, Susan Gallagher, Darren Clement, Alison Brind, Gill Watts, Mcdonald Mupudzi, Mark Wright, Jane Gitahi, Fiona Gordon, Denis Gocher, Esther Unitt, Hilary Pateman, Sally Batham, Toby Delahooke, Allister Grant, Jill Conder, Andrew Higham, Mark Cox, Lynn O'Donohoe, Lynn Currie, Alistair King, Metod Oblak, Carole Collins, Simon Whalley, Marie Quinn, Yolanda Baird, Isobel Amey, Jocelyn Fraser, Andy Li, Donna Cotterill, Andrew Bell, Amit Singhal, Ian Gee, Sandra Greer, Yeng Ang, Rupert Ransford, Joanna Allison, James Gotto, Simon Dyer, Helen Sweeting, Charles Millson, Giancarlo Labbadia, Maria Consiglia Bragazzi, Pietro Andreone, Francesco Azzaroli, Andrea Galli, Mirko Tarocchi, Antonio Gasbarrini, Antonio Grieco, Giuseppe Marrone, Maria Francesca Donato, Luca Valenti, Luca Maroni, Cristina Rigamonti, Antonino Picciotto, Carbone, M, Nardi, A, Flack, S, Carpino, G, Varvaropoulou, N, Gavrila, C, Spicer, A, Badrock, J, Bernuzzi, F, Cardinale, V, Ainsworth, H, Heneghan, M, Thorburn, D, Bathgate, A, Jones, R, Neuberger, J, Battezzati, P, Zuin, M, Taylor-Robinson, S, Donato, M, Kirby, J, Mitchell-Thain, R, Floreani, A, Sampaziotis, F, Muratori, L, Alvaro, D, Marzioni, M, Miele, L, Marra, F, Giannini, E, Gaudio, E, Ronca, V, Bonato, G, Cristoferi, L, Malinverno, F, Gerussi, A, Stocken, D, Cordell, H, Hirschfield, G, Alexander, G, Sandford, R, Jones, D, Invernizzi, P, Mells, G, Thomas, C, Rahman, M, Yapp, T, Lye Ch'ng, C, Harrison, M, Sturgess, R, Galaska, R, Healey, C, Whiteman, J, Czaijkowski, M, Gray, C, Gunasekera, A, Gyawli, P, Premchand, P, Mann, S, Elliott, K, Kapur, K, Watson, A, Foster, G, Trembling, P, Subhani, J, Harvey, R, Mccorry, R, Adgey, C, Hobson, L, Mulvaney-Jones, C, Evans, R, Mathialahan, T, Ramanaden, D, Gasem, J, Van Duyvenvoorde, G, Shorrock, C, Seward, K, Southern, P, Tibble, J, Penn, R, Gorard, D, Maiden, J, Damant, R, Palegwala, A, Jones, S, Dolwani, S, Prince, M, Silvestre, V, Foxton, M, Dungca, E, Mitchison, H, Wheatley, N, Gooding, I, Doyle, H, Karmo, M, Kent, M, Saksena, S, Braim, D, Patel, M, Lord, S, Ede, R, Paton, A, Austin, A, Lancaster, N, Sayer, J, Gibbins, A, Hogben, K, Hovell, C, Fisher, N, Carter, M, Koss, K, Musselwhite, J, Muscariu, F, Piotreowicz, A, Mckay, A, Grimley, C, Neal, D, Ting Tan, L, Lim, G, Brighton, J, Foale, C, Ala, A, Saeed, A, Flahive, K, Wood, G, Townshend, P, Ford, C, Brown, J, Kordula, J, Bowles, J, Wilkinson, M, Palmer, C, Ramage, J, Gordon, H, Featherstone, J, Ridpath, J, Ngatchu, T, Levi, S, Shaukat, S, Sadeghian, J, Shidrawi, R, Williams, B, Abouda, G, Duggan, C, Hynes, A, Narain, M, Rees, I, Salam, I, Crossey, M, Brown, A, Macnicol, C, Williams, S, Wilhelmsen, E, Banim, P, Raymode, P, Chilton, A, Das, D, Lee, H, Curtis, H, Gess, M, Durant, E, Drake, I, Bishop, R, Davies, M, Aldersley, M, Ncube, N, Mcnair, A, Srirajaskanthan, R, Sen, S, Casey, R, Bird, G, Mendall, M, Cowley, C, Barnardo, A, Kitchen, P, Yoong, K, Amore, K, Sirdefield, D, Orpe, J, Mathew, R, Macfaul, G, Wrigth, A, Shah, A, Evans, C, Keggans, J, Bird, B, Baxter, G, Saha, S, Pollock, K, Hughes, M, Bramley, P, Grieve, E, Young, K, Fraser, A, Mukhopadhya, A, Ocker, K, Mills, P, Hines, F, Shallcross, C, Wilkins, J, Grellier, L, Campbell, S, Martin, K, Innes, C, Shepherd, A, Rushbrook, S, Valliani, T, Przemioslo, R, Fairlamb, H, Macdonald, C, Eastick, A, Metcalf, J, Tanqueray, E, Shmueli, U, Holbrook, B, Davis, A, Browning, J, Naqvi, A, Walker, K, Lee, T, Verheyden, J, Slininger, S, Ryder, S, Chapman, R, Collier, J, O'Donnell, D, Stafford, L, Williamson, K, Kent, L, Klass, H, Ninkovic, M, March, L, Cramp, M, Simpson, D, Dickson, C, Sharer, N, Hayes, M, Goggin, P, Quinne, M, Pearson, S, Hoeroldt, B, Jones, L, Wright, A, Booth, J, Loftus, A, Lipscomb, G, Dewhurst, H, Gunter, E, Williams, E, Fouracres, A, Farrington, L, Graves, L, Hussaini, H, Stableforth, B, Marriott, S, Ayres, R, Leoni, M, Burroughs, A, Marshall, E, Tyrer, D, Lombard, M, Patanwala, I, Dali-Kemmery, L, Lambourne, V, Maltby, J, Vyas, S, Colley, J, Shinder, B, Singhal, S, Jones, J, Mills, M, Gleeson, D, Carnahan, M, Butterworth, J, Boulton, K, Taylor, N, George, K, Harding, T, Tregonning, J, Douglass, A, Brown, C, Clifford, G, Panter, S, Gocher, D, Shearman, J, Bray, G, Hamilton, M, Butcher, G, Forton, D, Mclindon, J, Curtis, J, Shewan, T, Cowan, M, Whatley, G, Nasseri, M, Grover, B, Sivaramakrishnan, N, Ducker, S, Houghton, K, Griffiths, L, Tripoli, S, Pitcher, M, Shpuza, E, White, N, Ghosh, D, Douds, A, Green, M, Brookes, M, Cumlat, L, Wong, V, Warner, K, Netherton, K, Mandal, A, Jain, S, Gupta, H, Sanghi, P, Pereira, S, Gunson, B, Lim, R, Gallagher, S, Clement, D, Brind, A, Watts, G, Mupudzi, M, Wright, M, Gitahi, J, Gordon, F, Unitt, E, Pateman, H, Batham, S, Delahooke, T, Grant, A, Conder, J, Higham, A, Cox, M, O'Donohoe, L, Currie, L, King, A, Oblak, M, Collins, C, Whalley, S, Quinn, M, Baird, Y, Amey, I, Fraser, J, Li, A, Cotterill, D, Bell, A, Singhal, A, Gee, I, Greer, S, Ang, Y, Ransford, R, Allison, J, Gotto, J, Dyer, S, Sweeting, H, Millson, C, Labbadia, G, Bragazzi, M, Andreone, P, Azzaroli, F, Galli, A, Tarocchi, M, Gasbarrini, A, Grieco, A, Marrone, G, Valenti, L, Maroni, L, Rigamonti, C, Picciotto, A, Sampaziotis, Fotios [0000-0003-0812-7586], Sandford, Richard [0000-0002-7437-0560], Apollo - University of Cambridge Repository, Carbone, Marco, Nardi, Alessandra, Flack, Steve, Carpino, Guido, Varvaropoulou, Nikoletta, Gavrila, Caiu, Spicer, Ann, Badrock, Jonathan, Bernuzzi, Francesca, Cardinale, Vincenzo, Ainsworth, Holly F, Heneghan, Michael A, Thorburn, Dougla, Bathgate, Andrew, Jones, Rebecca, Neuberger, James M, Battezzati, Pier Maria, Zuin, Massimo, Taylor-Robinson, Simon, Donato, Maria F, Kirby, John, Mitchell-Thain, Robert, Floreani, Annarosa, Sampaziotis, Fotio, Muratori, Luigi, Alvaro, Domenico, Marzioni, Marco, Miele, Luca, Marra, Fabio, Giannini, Edoardo, Gaudio, Eugenio, Ronca, Vincenzo, Bonato, Giulia, Cristoferi, Laura, Malinverno, Federica, Gerussi, Alessio, Stocken, Deborah D, Cordell, Heather J, Hirschfield, Gideon M, Alexander, Graeme J, Sandford, Richard N, Jones, David E, Invernizzi, Pietro, Mells, George F, Thomas, Caradog, Rahman, Meshbah, Yapp, Tom, Lye Ch'ng, Chin, Harrison, Melanie, Sturgess, Richard, Galaska, Roman, Healey, Chri, Whiteman, Jessica, Czaijkowski, Marek, Gray, Catherine, Gunasekera, Anton, Gyawli, Pranab, Premchand, Purushothaman, Mann, Steven, Elliott, Keith, Kapur, Kapil, Watson, Alan, Foster, Graham, Trembling, Paul, Subhani, Javaid, Harvey, Rory, McCorry, Roger, Adgey, Carolyn, Hobson, Lucie, Mulvaney-Jones, Caroline, Evans, Richard, Mathialahan, Thiriloganathan, Ramanaden, David, Gasem, Jaber, Van Duyvenvoorde, Greta, Shorrock, Christopher, Seward, Katie, Southern, Paul, Tibble, Jeremy, Penn, Ruth, Gorard, David, Maiden, Jane, Damant, Rose, Palegwala, Altaf, Jones, Susan, Alexander, Graeme, Mells, George, Sandford, Richard, Dolwani, Sunil, Prince, Martin, Silvestre, Valeria, Foxton, Matthew, Dungca, Eleanor, Mitchison, Harriet, Wheatley, Natalie, Gooding, Ian, Doyle, Helen, Karmo, Mazn, Kent, Melanie, Saksena, Sushma, Braim, Delyth, Patel, Minesh, Lord, Susan, Ede, Roland, Paton, Alison, Austin, Andrew, Lancaster, Nicola, Sayer, Joanna, Gibbins, Andrew, Hogben, Karen, Hovell, Chri, Fisher, Neil, Carter, Martyn, Koss, Konrad, Musselwhite, Janine, Muscariu, Florin, Piotreowicz, Andrzej, McKay, Alexandra, Grimley, Charle, Neal, David, Ting Tan, Lai, Lim, Guan, Brighton, Jacqueline, Foale, Carole, Ala, Aftab, Saeed, Athar, Flahive, Kerry, Wood, Gordon, Townshend, Paula, Ford, Chri, Brown, Jonathan, Kordula, Jean, Bowles, Jane, Wilkinson, Mark, Palmer, Caroline, Ramage, John, Gordon, Harriet, Featherstone, Jame, Ridpath, Jo, Ngatchu, Theodore, Levi, Sa, Shaukat, Syed, Sadeghian, Joy, Shidrawi, Ray, Williams, Bronwen, Abouda, George, Jones, Sarah, Duggan, Claire, Hynes, Abigail, Narain, Mark, Rees, Ian, Salam, Imroz, Crossey, Mary, Brown, Ashley, MacNicol, Carolyn, Williams, Simon, Wilhelmsen, Elva, Banim, Paul, Raymode, Parizade, Chilton, Andrew, Das, Debasish, Lee, Hye-Jeong, Curtis, Howard, Heneghan, Michael, Gess, Marku, Durant, Emma, Drake, I.M., Bishop, Rebecca, Davies, Mervyn, Aldersley, Mark, Ncube, Noma, McNair, Alistair, Srirajaskanthan, Raj, Sen, Sambit, Casey, Rebecca, Bird, George, Mendall, Mike, Cowley, Caroline, Barnardo, Adrian, Kitchen, Paul, Yoong, Kevin, Amore, Kelly, Sirdefield, Dawn, Orpe, Jacky, Mathew, Ray, MacFaul, George, Wrigth, Aruna, Shah, Amir, Evans, Chri, Keggans, Janie, Bird, Bridget, Baxter, Gwen, Saha, Subrata, Pollock, Katharine, Hughes, Maggie, Bramley, Peter, Grieve, Emma, Young, Karin, Fraser, Andrew, Mukhopadhya, Ashi, Ocker, Kate, Mills, Peter, Hines, Franci, Shallcross, Chri, Wilkins, Joy, Grellier, Leonie, Campbell, Stewart, Martin, Kirsty, Innes, Caron, Shepherd, Alan, Rushbrook, Simon, Valliani, Talal, Przemioslo, Robert, Fairlamb, Helen, Macdonald, Chri, Eastick, Anne, Metcalf, Jane, Tanqueray, Elizabeth, Shmueli, Udi, Holbrook, Becky, Davis, Andrew, Browning, Julie, Naqvi, Asifabba, Walker, Kirsten, Lee, Tom, Verheyden, Juliette, Slininger, Susan, Ryder, Stephen D, Chapman, Roger, Collier, Jane, O'Donnell, Denise, Stafford, Lizzie, Williamson, Kate, Kent, Linda, Klass, Howard, Ninkovic, Mary, March, Linda, Cramp, Matthew, Simpson, Diane, Dickson, Christine, Sharer, Nichola, Hayes, Maria, Goggin, Patrick, Quinne, Mary, Pearson, Sallyanne, Hoeroldt, Barbara, Jones, Linda, Wright, Alice, Booth, Jonathan, Loftus, Alison, Lipscomb, George, Dewhurst, Hannah, Gunter, Emma, Williams, Earl, Fouracres, Anna, Farrington, Liz, Graves, Lyn, Hussaini, Hyder, Stableforth, Bill, Marriott, Suzie, Ayres, Reuben, Leoni, Marina, Burroughs, Andrew, Marshall, Eileen, Tyrer, David, Martin, Kate, Lombard, Martin, Patanwala, Imran, Dali-Kemmery, Lola, Lambourne, Victoria, Maltby, Julia, Vyas, Samir, Colley, Julie, Shinder, Bal, Singhal, Saket, Jones, Jayne, Mills, Marisa, Gleeson, Dermot, Carnahan, Mandy, Butterworth, Jeff, Boulton, Kerenza, Taylor, Natalie, George, Keith, Harding, Tim, Tregonning, Julie, Douglass, Andrew, Brown, Carly, Clifford, Gayle, Panter, Simon, Gocher, Denise, Shearman, Jeremy, Bray, Gary, Hamilton, Maria, Butcher, Graham, Forton, Daniel, Mclindon, John, Curtis, Janette, Das, Debashi, Shewan, Tracey, Cowan, Matthew, Whatley, Gregory, Nasseri, Mariam, Grover, Bob, Sivaramakrishnan, Nurani, Ducker, Samantha, Houghton, Kathryn, Jones, David, Griffiths, Laura, Tripoli, Sherill, Pitcher, Maxton, Shpuza, Ervin, White, Nikki, Ghosh, Deb, Douds, Andrew, Green, Marie, Brookes, Matthew, Cumlat, Lourde, Wong, Voi Shim, Warner, Karen, Netherton, Kimberley, Mandal, Adtya, Jain, Snjiv, Gupta, Hemant, Sanghi, Pradeep, Pereira, Steve, Neuberger, Jame, Gunson, Bridget, Hirschfield, Gideon, Lim, Reina Teegan, Gallagher, Susan, Clement, Darren, Brind, Alison, Watts, Gill, Mupudzi, Mcdonald, Wright, Mark, Gitahi, Jane, Gordon, Fiona, Gocher, Deni, Unitt, Esther, Pateman, Hilary, Batham, Sally, Delahooke, Toby, Grant, Allister, Conder, Jill, Higham, Andrew, Cox, Mark, O'Donohoe, Lynn, Currie, Lynn, King, Alistair, Oblak, Metod, Collins, Carole, Whalley, Simon, Quinn, Marie, Baird, Yolanda, Amey, Isobel, Fraser, Jocelyn, Li, Andy, Cotterill, Donna, Bell, Andrew, Singhal, Amit, Gee, Ian, Greer, Sandra, Ang, Yeng, Ransford, Rupert, Allison, Joanna, Gotto, Jame, Dyer, Simon, Sweeting, Helen, Millson, Charle, Labbadia, Giancarlo, Bragazzi, Maria Consiglia, Andreone, Pietro, Azzaroli, Francesco, Galli, Andrea, Tarocchi, Mirko, Gasbarrini, Antonio, Grieco, Antonio, Marrone, Giuseppe, Donato, Maria Francesca, Valenti, Luca, Maroni, Luca, Rigamonti, Cristina, Picciotto, Antonino, and Medical Research Council (MRC)

Subjects
Male, Cholagogues and Choleretics, Cirrhosis, medicine.medical_treatment, PROGRESSION, Liver transplantation, PHENOTYPE, Gastroenterology, UDCA, 0302 clinical medicine, Primary biliary cirrhosis, Risk Factors, Medicine, Age of Onset, CIRRHOSIS, TREE, OUTCOMES, Settore MED/12 - Gastroenterologia, medicine.diagnostic_test, Liver Cirrhosis, Biliary, Ursodeoxycholic Acid, Area under the curve, URSODIOL, Middle Aged, Ursodeoxycholic acid, Treatment Outcome, Primary biliary cholangitis, ursodeoxycholic acid, 030220 oncology & carcinogenesis, Liver biopsy, Area Under Curve, 030211 gastroenterology & hepatology, Female, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, CONTROLLED-TRIAL, Hepatology, Decision Support Techniques, Time-to-Treatment, Biliary injury, 03 medical and health sciences, Internal medicine, Humans, Transaminases, Science & Technology, Gastroenterology & Hepatology, Italian PBC Study Group and the UK–PBC Consortium, business.industry, Bilirubin, medicine.disease, Alkaline Phosphatase, ROC Curve, CELLS, Linear Models, business
Abstract

Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p

Published
2018

15. A retrospective study assessing fully covered metal stents as first-line management for malignant biliary strictures

Author

Bruce Macfarlane, Jeremy Woodward, A King, Joshua E. Elias, Alexander Gimson, Gareth Corbett, William Gelson, Anthony Leahy, Fotios Sampaziotis, William J. Griffiths, and Mohamed Shariff

Subjects
Adult, Male, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Self Expandable Metallic Stents, Cholestasis, Intrahepatic, Cholangiocarcinoma, Self-expandable metallic stent, Humans, Medicine, Survival rate, Aged, Retrospective Studies, Aged, 80 and over, Cholangiopancreatography, Endoscopic Retrograde, Endoscopic retrograde cholangiopancreatography, Hepatology, medicine.diagnostic_test, business.industry, Carcinoma, Gastroenterology, Stent, Drug-Eluting Stents, Retrospective cohort study, Bacterial Infections, Middle Aged, medicine.disease, Surgery, Pancreatic Neoplasms, Survival Rate, Exact test, Bile Duct Neoplasms, Pancreatitis, Female, Complication, business, Plastics
Abstract

OBJECTIVES Fully covered self-expanding metal stents (FCSEMS) constitute the first type of metal stent that can easily be removed endoscopically and/or intraoperatively, which may be advantageous in the management of distal malignant biliary strictures (DMBS). To assess the efficacy of FCSEMS as first-line treatment for DMBS, we compared patency, survival and complication rates between FCSEMS, uncovered self-expanding metal stents (USEMS) and plastic stents (PS). METHODS This was a multicentre retrospective study of 315 consecutive patients with DMBS, who underwent endoscopic retrograde cholangiopancreatography and stenting (FCSEMS, USEMS or PS) at two hospitals between 1 January 2007 and 31 December 2013. Stent patency and patient survival were compared using the Kaplan-Meier method; complication rates were compared using Fisher's exact test; and Cox regression analysis was used to screen for confounding factors. RESULTS FCSEMS were associated with prolonged stent patency (median=145 days) compared with USEMS (median=110 days, P

Published
2015

16. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation

Author

Nicholas R.F. Hannan, Tom H. Karlsen, Filipa A.C. Soares, William Gelson, E. Schrumpf, Ludovic Vallier, Graeme J.M. Alexander, Miguel Cardoso de Brito, Espen Melum, Alastair Baker, Arthur Kaser, Fotios Sampaziotis, J. Andrew Bradley, Pedro Madrigal, Kourosh Saeb-Parsy, Susan E. Davies, Alessandro Bertero, Sampaziotis, Fotios [0000-0003-0812-7586], Madrigal, Pedro [0000-0003-1959-8199], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Vallier, Ludovic [0000-0002-3848-2602], and Apollo - University of Cambridge Repository

Subjects
Biomedical Research, Induced Pluripotent Stem Cells, Biomedical Engineering, Bioengineering, Models, Biological, Applied Microbiology and Biotechnology, Cystic fibrosis, Article, Secretin, Biliary disease, 03 medical and health sciences, 0302 clinical medicine, Directed differentiation, Drug Discovery, Alagille syndrome, Humans, Medicine, Biliary Tract, Induced pluripotent stem cell, Cells, Cultured, 030304 developmental biology, 0303 health sciences, business.industry, Liver Diseases, Polycystic liver disease, medicine.disease, 3. Good health, Immunology, Cancer research, Molecular Medicine, Alkaline phosphatase, 030211 gastroenterology & hepatology, business, Biotechnology
Abstract

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.

Published
2015

17. Potential of human induced pluripotent stem cells in studies of liver disease

Author

Charis-Patricia Segeritz, Fotios Sampaziotis, Ludovic Vallier, Sampaziotis, Fotios [0000-0003-0812-7586], Vallier, Ludovic [0000-0002-3848-2602], and Apollo - University of Cambridge Repository

Subjects
Cell type, Cirrhosis, Induced Pluripotent Stem Cells, Biology, 03 medical and health sciences, Liver disease, 0302 clinical medicine, medicine, Humans, Proteostasis Deficiencies, Human Induced Pluripotent Stem Cells, Induced pluripotent stem cell, Drug toxicity, 030304 developmental biology, 0303 health sciences, Hepatology, Liver Diseases, medicine.disease, In vitro, 3. Good health, Underlying disease, Immunology, Hepatocytes, Cancer research, 030211 gastroenterology & hepatology, Chemical and Drug Induced Liver Injury
Abstract

Liver disease is a leading cause of death in the Western world. However, our insight into the underlying disease mechanisms and the development of novel therapeutic agents has been hindered by limited availability of primary tissue, intraspecies variability associated with the use of animal models, and reduced long-term viability of isolated and diseased liver cells. The emergence of human induced pluripotent stem cells and differentiation protocols to generate hepatocyte-like cells has opened the possibility of addressing these issues. Here, we discuss the recent progress and potential in the production of various cell types constituting the liver and their applications to model liver diseases and test drug toxicity in vitro.

Published
2015

18. Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids

Author

Kim B. Jensen, Nicholas R.F. Hannan, Johannes Bargehr, Olivia C. Tysoe, William Gelson, Ludovic Vallier, Edmund Godfrey, María J Gómez-Vázquez, Susan E. Davies, Sanjay Sinha, Negar Pirmadjid, Casey A. Rimland, Mariëlle C. F. Zonneveld, Marianne Terndrup Pedersen, Kirsten E. Snijders, Athina E. Markaki, N.L. Berntsen, Ingrid Simonic, Kourosh Saeb-Parsy, Laura Valestrand, Nikitas Georgakopoulos, Stephanie Brown, Richard L. Gieseck, Thomas A. Wynn, Pedro Madrigal, Graeme J.M. Alexander, Daniel Ortmann, Matthias Zilbauer, Fotios Sampaziotis, Alessandro Bertero, Tom H. Karlsen, Miguel Cardoso de Brito, Stephen J. Sawiak, Wenmiao Shu, Sara Upponi, Paulina M. Materek, Alexander W. Justin, Espen Melum, Alexander Ross, Loukia Yiangou, Matthias Pawlowski, Gregor Skeldon, and John Casey

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Cell Transplantation, Cystic Fibrosis Transmembrane Conductance Regulator, In Vitro Techniques, Regenerative medicine, General Biochemistry, Genetics and Molecular Biology, Cholangiocyte, 03 medical and health sciences, Mice, Cholestasis, Secretin, Biliary atresia, Bile Ducts, Extrahepatic, TA164, medicine, Journal Article, Animals, Humans, Regeneration, Video-Audio Media, Biliary Tract, Keratin-19, Common bile duct, Tissue Engineering, Tissue Scaffolds, business.industry, Gallbladder, Keratin-7, Epithelial Cells, General Medicine, gamma-Glutamyltransferase, medicine.disease, Transplantation, Organoids, 030104 developmental biology, medicine.anatomical_structure, Biliary tract, business, Somatostatin
Abstract

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 $\textit{in vivo}$ 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 $\textit{in vitro}$.

Published
2017

19. Optimized inducible shRNA and CRISPR/Cas9 platforms for in vitro studies of human development using hPSCs

Author

Alessandro, Bertero, Matthias, Pawlowski, Daniel, Ortmann, Kirsten, Snijders, Loukia, Yiangou, Miguel, Cardoso de Brito, Stephanie, Brown, William G, Bernard, James D, Cooper, Elisa, Giacomelli, Laure, Gambardella, Nicholas R F, Hannan, Dharini, Iyer, Fotios, Sampaziotis, Felipe, Serrano, Mariëlle C F, Zonneveld, Sanjay, Sinha, Mark, Kotter, and Ludovic, Vallier

Subjects
Fetal Proteins, Induced Pluripotent Stem Cells, Nuclear Proteins, POU5F1, Cell Differentiation, T, brachyury, OCT4, Stem Cells and Regeneration, Gene Knockout Techniques, DPY30, shRNA, Cyclin D, Humans, Clustered Regularly Interspaced Short Palindromic Repeats, Human pluripotent stem cells, CRISPR-Cas Systems, Genetic Engineering, T-Box Domain Proteins, Octamer Transcription Factor-3, CRISPR/Cas9, Cells, Cultured, Embryonic Stem Cells, Transcription Factors
Abstract

Inducible loss of gene function experiments are necessary to uncover mechanisms underlying development, physiology and disease. However, current methods are complex, lack robustness and do not work in multiple cell types. Here we address these limitations by developing single-step optimized inducible gene knockdown or knockout (sOPTiKD or sOPTiKO) platforms. These are based on genetic engineering of human genomic safe harbors combined with an improved tetracycline-inducible system and CRISPR/Cas9 technology. We exemplify the efficacy of these methods in human pluripotent stem cells (hPSCs), and show that generation of sOPTiKD/KO hPSCs is simple, rapid and allows tightly controlled individual or multiplexed gene knockdown or knockout in hPSCs and in a wide variety of differentiated cells. Finally, we illustrate the general applicability of this approach by investigating the function of transcription factors (OCT4 and T), cell cycle regulators (cyclin D family members) and epigenetic modifiers (DPY30). Overall, sOPTiKD and sOPTiKO provide a unique opportunity for functional analyses in multiple cell types relevant for the study of human development., Highlighted article: Novel optimized inducible knockdown and knockout platforms are developed and used to assess gene function in human pluripotent stem cells and their differentiated progeny.

Published
2016

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