In vitro modelling of biliary development and diseases
Lead Research Organisation:
University of Cambridge
Department Name: Surgery
Abstract
Bile is a toxic fluid produced in the liver and transferred through tubular structures known as bile ducts to the gut, where it helps with fat absorption. In bile duct disorders (cholangiopathies), the bile ducts fail to contain and transfer bile effectively. As a result, toxic bile leaks out of the ducts and accumulates in the liver causing significant damage. Unfortunately, our understanding of the exact mechanisms leading to biliary disease is very limited. Research in the field is hindered by technical difficulties in obtaining and maintaining live bile duct samples in the laboratory and the lack of animal models faithfully reproducing the disease. Nevertheless, the need to decipher the disease mechanisms, towards developing new diagnostic tests and treatment options is very pressing. Bile duct disorders account for a major proportion of all liver disease, carrying significant mortality. The only available treatment is liver transplantation, a lifesaving but expensive and challenging operation, requiring lifelong medication and follow-up and complicated by the national shortage of liver donors.
Alagille syndrome (AGS) is an inherited disorder. Although it involves multiple organs, biliary disease caused by poor bile duct development in pregnancy and early life constitutes the most common clinical manifestation. Liver transplantation remains the only treatment option. Compared to other bile duct disorders the study of AGS has two important advantages: Primarily, the disease mechanism is not completely unknown, as the hereditary mutation causing it has already been described. Secondarily, in view of the close association between AGS and bile duct development, elucidating the disease mechanism will provide significant information on how bile ducts normally develop. Duct development is implicated to some extent in all childhood biliary disorders leading to paediatric liver transplantation. Therefore, studying AGS may advance our knowledge on a whole group of biliary diseases.
The aim of this project is to develop a novel method for generating large amounts of fully functional bile duct replicas in the laboratory. The resulting ducts will provide an excellent model to study any biliary disease, test and develop new therapies. I propose applying this method for generating the first proof-of-principle disease model for AGS and elucidating the disease mechanism. I have already made significant progress towards achieving this goal. Using the technology of stem cells, I have successfully created functional bile duct replicas, starting from healthy individuals' skin samples. I intend to use the same approach to generate and study bile ducts from AGS patients. Once the ducts have been created, I will use cutting edge technology to decipher the series of events leading to AGS and attempt to 'rescue' the diseased ducts by intervening and altering these events.
This project will shed light on the mechanisms driving AGS, facilitating the development of new tests for identifying the disease in early stages, new markers for predicting its course and new treatment options alternative to liver transplantation. Ultimately, it will contribute to improving the patients' quality of life, reducing pressure on the transplant waiting list and changing AGS from an untreatable disease to a manageable condition. Furthermore, the platform described has the potential to generate large amounts of bile duct replicas from patients with any biliary disorder. Therefore, it will provide a powerful novel disease modelling tool for the benefit of any research group working on bile ducts, overcoming the difficulties related to lack of biliary tissue and paving the road towards understanding and treating biliary disease in the future.
Alagille syndrome (AGS) is an inherited disorder. Although it involves multiple organs, biliary disease caused by poor bile duct development in pregnancy and early life constitutes the most common clinical manifestation. Liver transplantation remains the only treatment option. Compared to other bile duct disorders the study of AGS has two important advantages: Primarily, the disease mechanism is not completely unknown, as the hereditary mutation causing it has already been described. Secondarily, in view of the close association between AGS and bile duct development, elucidating the disease mechanism will provide significant information on how bile ducts normally develop. Duct development is implicated to some extent in all childhood biliary disorders leading to paediatric liver transplantation. Therefore, studying AGS may advance our knowledge on a whole group of biliary diseases.
The aim of this project is to develop a novel method for generating large amounts of fully functional bile duct replicas in the laboratory. The resulting ducts will provide an excellent model to study any biliary disease, test and develop new therapies. I propose applying this method for generating the first proof-of-principle disease model for AGS and elucidating the disease mechanism. I have already made significant progress towards achieving this goal. Using the technology of stem cells, I have successfully created functional bile duct replicas, starting from healthy individuals' skin samples. I intend to use the same approach to generate and study bile ducts from AGS patients. Once the ducts have been created, I will use cutting edge technology to decipher the series of events leading to AGS and attempt to 'rescue' the diseased ducts by intervening and altering these events.
This project will shed light on the mechanisms driving AGS, facilitating the development of new tests for identifying the disease in early stages, new markers for predicting its course and new treatment options alternative to liver transplantation. Ultimately, it will contribute to improving the patients' quality of life, reducing pressure on the transplant waiting list and changing AGS from an untreatable disease to a manageable condition. Furthermore, the platform described has the potential to generate large amounts of bile duct replicas from patients with any biliary disorder. Therefore, it will provide a powerful novel disease modelling tool for the benefit of any research group working on bile ducts, overcoming the difficulties related to lack of biliary tissue and paving the road towards understanding and treating biliary disease in the future.
Technical Summary
Cholangiopathies represent a leading cause for liver disease and transplantation. Treatment options are very limited and research in the field is hindered by poor primary tissue access and lack of robust disease models. Alagille Syndrome (AGS) is a monogenic, syndromic infantile cholangiopathy. It is caused by JAG1 or Notch2 gene mutations leading to poor biliary tree development, paucity of bile ducts and hepatic impairment. The pathogenesis of AGS remains elusive and liver transplantation provides the only available therapy.
We propose establishing a novel platform for in vitro modelling of biliary diseases, based on a methodology we developed for generating cholangiocytes from patient derived human Induced Pluripotent Stem Cells (hIPSCs). We will validate this platform by developing the first proof-of-principle in vitro model for AGS, towards exploring the role of JAG-Notch signalling in biliary development and disease. The disease phenotype will be reproduced in vitro using AGS-hIPSCs undergoing biliary differentiation and organoid formation in 3D culture conditions. To demonstrate the association between JAG-Notch signalling and our in vitro phenotype, we will correct the JAG mutation in AGS hIPSCs and silence Notch signalling in generic hIPSCs expecting rescue and reproduction of the AGS phenotype respectively. We will then use CHIP assays, genome wide analysis and pathway inducers/inhibitors to characterise the transcriptional network regulated by Notch in biliary development and identify cross-talk with other key pathways.
Differentiation of hIPSC to cholangiocytes will increase our insight in biliary development, overcome limitations due to lack of primary tissue and provide large amounts of autologous biliary epithelial cells for the study of cholangiopathies. Modelling AGS in vitro will elucidate the disease pathogenesis, promote the generation of novel prognostic, diagnostic and therapeutic modalities and pioneer in vitro biliary disease modelling.
We propose establishing a novel platform for in vitro modelling of biliary diseases, based on a methodology we developed for generating cholangiocytes from patient derived human Induced Pluripotent Stem Cells (hIPSCs). We will validate this platform by developing the first proof-of-principle in vitro model for AGS, towards exploring the role of JAG-Notch signalling in biliary development and disease. The disease phenotype will be reproduced in vitro using AGS-hIPSCs undergoing biliary differentiation and organoid formation in 3D culture conditions. To demonstrate the association between JAG-Notch signalling and our in vitro phenotype, we will correct the JAG mutation in AGS hIPSCs and silence Notch signalling in generic hIPSCs expecting rescue and reproduction of the AGS phenotype respectively. We will then use CHIP assays, genome wide analysis and pathway inducers/inhibitors to characterise the transcriptional network regulated by Notch in biliary development and identify cross-talk with other key pathways.
Differentiation of hIPSC to cholangiocytes will increase our insight in biliary development, overcome limitations due to lack of primary tissue and provide large amounts of autologous biliary epithelial cells for the study of cholangiopathies. Modelling AGS in vitro will elucidate the disease pathogenesis, promote the generation of novel prognostic, diagnostic and therapeutic modalities and pioneer in vitro biliary disease modelling.
Planned Impact
Social impact: Currently, treatments options for biliary diseases are very limited and the only available treatment for liver disease in Alagille Syndrome (AGS) is liver transplantation, a lifesaving but challenging procedure, requiring long-term medication and follow-up and complicated by the national shortage of grafts. This project will generate the first robust in vitro modelling platform for AGS and biliary diseases, providing a novel tool that will promote research in the field of cholangiopathies. Furthermore, it will increase our insight in the pathogenesis of AGS identifying potential diagnostic, prognostic and therapeutic markers. These advances will constitute the first step towards developing new treatments alternative to liver transplantation, improving the patients' quality of life and reducing pressure on the liver transplant waiting list, not only for AGS but ultimately for the whole spectrum of biliary diseases.
Non Academic beneficiaries: The proposal is likely to generate commercially exploitable findings. The platform generated by this project will provide a solution to the challenges of biliary differentiation of stem cells, in vitro biliary disease modelling and drug screening for cholangiopathies. Several companies including GSK, Vertex, DefiniGEN, AstraZeneca, and pFIZER have already shown an interest in cell types generated by the Vallier group, available for disease modelling. HIPSCs-derived cholangiocytes could constitute excellent candidates for such commercial applications.
Economic impact: Liver transplantation remains the only treatment option for the majority of cholangiopathies. The very high cost of the procedure (~ £56,000/ procedure), combined with the cost of the life-long immunosuppression therapy required and multiple diagnostic tests or hospital admissions, associated with procedure complications (~ £81,000/ patient), constitute a significant economic burden for the NHS (Data from the Specialised Commissioning Team report: Organs for Transplant: Costs and Savings for the NHS, October, 2010). The development of a novel modelling platform for biliary disease will promote the identification of novel therapeutic targets, enable screening for new drugs and ultimately provide alternative treatments to liver transplantation, reducing the economic impact of biliary disease on the NHS.
Experiments on animals and animal welfare: The extensive use of animal models in research has given rise to significant ethical and societal concerns. To address these concerns every effort is made to replace and reduce the need for animals in research as well as safeguard their welfare. This initiative is coordinated by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). The development of an in vitro disease modelling platform will contribute significantly towards this cause and limit research costs by reducing the use of animals in the study of biliary disorders or even replacing in vivo models in some cases.
Strategic Impact: This project focuses on advancing the field of regenerative medicine by generating a novel protocol for biliary differentiation of stem cells and translating this basic research in clinical applications by developing a novel disease modelling platform. Both of these areas of focus have been identified as priority targets in the MRC Strategic Plan 2009-2014. Close collaborators involved in the UK PBC (Primary Biliary Cirrhosis) consortium, have already expressed interest in expanding the impact of our research even further, using our platform to facilitate the interpretation of data generated by population wide studies in PBC, a strategic target supported by the recent MRC award for Primary Biliary Cirrhosis Research.
Non Academic beneficiaries: The proposal is likely to generate commercially exploitable findings. The platform generated by this project will provide a solution to the challenges of biliary differentiation of stem cells, in vitro biliary disease modelling and drug screening for cholangiopathies. Several companies including GSK, Vertex, DefiniGEN, AstraZeneca, and pFIZER have already shown an interest in cell types generated by the Vallier group, available for disease modelling. HIPSCs-derived cholangiocytes could constitute excellent candidates for such commercial applications.
Economic impact: Liver transplantation remains the only treatment option for the majority of cholangiopathies. The very high cost of the procedure (~ £56,000/ procedure), combined with the cost of the life-long immunosuppression therapy required and multiple diagnostic tests or hospital admissions, associated with procedure complications (~ £81,000/ patient), constitute a significant economic burden for the NHS (Data from the Specialised Commissioning Team report: Organs for Transplant: Costs and Savings for the NHS, October, 2010). The development of a novel modelling platform for biliary disease will promote the identification of novel therapeutic targets, enable screening for new drugs and ultimately provide alternative treatments to liver transplantation, reducing the economic impact of biliary disease on the NHS.
Experiments on animals and animal welfare: The extensive use of animal models in research has given rise to significant ethical and societal concerns. To address these concerns every effort is made to replace and reduce the need for animals in research as well as safeguard their welfare. This initiative is coordinated by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). The development of an in vitro disease modelling platform will contribute significantly towards this cause and limit research costs by reducing the use of animals in the study of biliary disorders or even replacing in vivo models in some cases.
Strategic Impact: This project focuses on advancing the field of regenerative medicine by generating a novel protocol for biliary differentiation of stem cells and translating this basic research in clinical applications by developing a novel disease modelling platform. Both of these areas of focus have been identified as priority targets in the MRC Strategic Plan 2009-2014. Close collaborators involved in the UK PBC (Primary Biliary Cirrhosis) consortium, have already expressed interest in expanding the impact of our research even further, using our platform to facilitate the interpretation of data generated by population wide studies in PBC, a strategic target supported by the recent MRC award for Primary Biliary Cirrhosis Research.
Organisations
- University of Cambridge (Fellow, Lead Research Organisation)
- Sparks Charity (Co-funder)
- University of Oslo (Collaboration)
- University of Newcastle (Collaboration)
- Addenbrooke's Hospital (Collaboration)
- Université Catholique de Louvain (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- University of Vienna (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
People |
ORCID iD |
Fotios Sampaziotis (Principal Investigator / Fellow) |
Publications
Justin A
(2018)
Advances in the generation of bioengineered bile ducts.
Justin AW
(2018)
Advances in the generation of bioengineered bile ducts.
in Biochimica et biophysica acta. Molecular basis of disease
Sampaziotis F
(2015)
Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.
in Nature biotechnology
Sampaziotis F
(2017)
Directed differentiation of human induced pluripotent stem cells into functional cholangiocyte-like cells.
in Nature protocols
Bargehr J
(2019)
Epicardial cells derived from human embryonic stem cells augment cardiomyocyte-driven heart regeneration.
in Nature biotechnology
Hannan NR
(2015)
Generation of Distal Airway Epithelium from Multipotent Human Foregut Stem Cells.
in Stem cells and development
Description | Academy of Medical Sciences - Starter Grant for Clinical Lecturers |
Amount | £30,000 (GBP) |
Funding ID | SGL019\1071, RG95713 |
Organisation | Academy of Medical Sciences (AMS) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2018 |
End | 08/2019 |
Description | Addenbrooke's Charitable Trust project grant |
Amount | £15,000 (GBP) |
Organisation | Addenbrooke's Charitable Trust (ACT) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2018 |
End | 02/2019 |
Description | EASL Young Investigator Travel Award |
Amount | € 600 (EUR) |
Organisation | European Association for the Study of the Liver (EASL) |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 04/2017 |
End | 04/2017 |
Description | EASL Young Investigator Travel Award |
Amount | € 600 (EUR) |
Organisation | European Association for the Study of the Liver (EASL) |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 04/2016 |
End | 04/2016 |
Description | Future Leaders Fellowship Scheme |
Amount | £1,288,889 (GBP) |
Organisation | United Kingdom Research and Innovation |
Sector | Public |
Country | United Kingdom |
Start | 10/2021 |
End | 09/2025 |
Description | Rosetrees Trust Interdisciplinary Research Project: 'Generation and transplantation of a bioengineered human bile duct' (ref: M787) |
Amount | £250,000 (GBP) |
Funding ID | M787 |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 08/2020 |
Description | St Catharine's College Travel Grant |
Amount | £600 (GBP) |
Organisation | University of Cambridge |
Department | St Catharine's College |
Sector | Academic/University |
Country | United Kingdom |
Start | 11/2015 |
End | 11/2015 |
Description | Theme-based Research Scheme |
Amount | HK$56,127,000 (HKD) |
Organisation | Research Grants Council Hong Kong |
Sector | Public |
Country | China |
Start | 01/2022 |
End | 12/2027 |
Title | In vitro model for Alagille Syndrome (AGS) |
Description | Using hIPSC-derived cholangiocytes we have been able to reproduce key features of AGS in vitro |
Type Of Material | Model of mechanisms or symptoms - in vitro |
Provided To Others? | No |
Impact | First in vitro model for AGS |
URL | http://www.nature.com/nbt/journal/v33/n8/abs/nbt.3275.html |
Title | In vitro model for Cystic Fibrosis (CF) liver disease |
Description | Using our stem cell derived cholangiocytes we were able to develop the first in vitro model for CF liver diasease. Using this model we were able to identify a novel therapeutic agent for CF liver disease. \ |
Type Of Material | Model of mechanisms or symptoms - human |
Provided To Others? | No |
Impact | 1. Reduced use of animals for the study of CF liver disease 2. Application as a platform for drug screening and drug development for CF liver disease 3. Future use by other groups for the study of the pathogenesis of CF liver disease |
URL | http://www.nature.com/nbt/journal/v33/n8/abs/nbt.3275.html |
Title | In vitro model for Polycystic Liver Disease (PLD) |
Description | Using hIPSC-derived cholangiocytes we have been able to recapitulate key fetaures of PLD and reproduce the effects of drugs used in clinical practice in vitro |
Type Of Material | Model of mechanisms or symptoms - in vitro |
Provided To Others? | No |
Impact | One of the first in vitro models for PLD This platform can be used for drug screening |
URL | http://www.nature.com/nbt/journal/v33/n8/abs/nbt.3275.html |
Title | Method for the generation of bio-engineered bile ducts |
Description | In close collaboration withthe department of engineering we developed a novel method for generating cast densified collagen tubes. We combined this method with our established technology (also developed by us) for generating bio-engineered tissue which resulted in the generation of the first bio-engineered bile duct. Our ducts were extensively validated in vitro and in vivo. |
Type Of Material | Technology assay or reagent |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | Novel method for generating cast densified collagen tubular scaffolds which can be applied to other organs extending beyond the biliary tree (taken forward by the department of Engineering) Novel method for transplantation of bio-engineered bile ducts generated with human cells in mice and therefore generating mice with a 'humanized' bile duct that could be used as models for biliary disease This method has contributed to a publication currently in revision in Nature Medicine, 2 conference poster awards and the BTS Medawar medal |
Title | Protocol for the generation of biliary tissue using in vitro generated cholangiocytes and biodegradable scaffolds |
Description | This method enables the population of biodegradable scaffolds with primary or hIPSC-derived cholangiocytes. The populated scaffolds resemble biliary tissue and could have broad applications for regenerative medicine purposes |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | 1. In vitro generated biliary tissue could be used for regenerative medicine applications, such as biliary reconstruction. Such interventions are currently significantly limited by the lack of healthy native biliary tissue 2. Regenerative medicine applications could have a significant impact on providing an alternative to liver transplantation and therefore reducing pressure on the liver transplant waiting list 3. This platform could be used as disease modeling or drug screening tool, reducing the need for animal experiments |
Title | Protocol for the generation of cholangiocytes from stem cells in vitro |
Description | We developed a novel protocol that allows the generation of functional cholangiocyte like cells from human Induced Pluripotent Stem Cells (hIPSCs). We have validated our protocol using 4 different hIPSC lines. Furthermore, we have compared our cells to primary human cholangiocytes (provided through our collaboration with the department of Surgery - University of Cambridge) using genome wide analyses and demonstrating significant overlap in their transcriptomic profiles |
Type Of Material | Cell line |
Provided To Others? | No |
Impact | Primary cholangiocytes can't be grown in vitro. Furthermore, there are significant differences in the phenotype of biliary disorders between human and mouse, rendering the in vivo studies in the mechanism of cholangiopathies challenging. Our protocol for the generation of stem cell derived cholangiocytes will contribute to: 1. Reduce the use of animals for the study of biliary disease 2. Provide a new in vitro modeling platform for cholangiopathies, overcoming challenges associated with in vivo models 3. Enable large scale/ high throughput studies which can't be performed using animal models (such as ChIP-sequencing) |
URL | http://www.nature.com/nbt/journal/v33/n8/abs/nbt.3275.html |
Title | Protocol for the propagation of primary extrahepatic cholangiocytes in vitro |
Description | One of the key challenges for research in bile duct disorders is the lack of appropriate in vitro platforms. We have recently partially addrressed this challenge by generating intra-hepatic cholangiocytes from human Induced Pluripotent Stem Cells. This new method expands on our previous technology and provides the first system for the propagation of extra-hepatic cholangiocytes in vitro |
Type Of Material | Cell line |
Provided To Others? | No |
Impact | 1. Reduced use of animal models 2. Disease modeling for extra-hepatic biliary disorders 3. Development of a drug screeing platform based on primary cells 4. This system enables large-scale studies such as ChIP-sequencing which were not available before due to the limited access to tissue and animals |
Title | Global gene expression profile dataset (microarray) for extrahepatic cholangiocyte organoids derived from primary biliary tissue |
Description | Micro-array dataset for global gene expression in primary extrahepatic cholangiocyte organoids (ECOs) propagated in vitro compared to undifferentiated stem cells and primary human bile duct tissue |
Type Of Material | Database/Collection of data |
Provided To Others? | No |
Impact | This is the first dataset characterizing the transcriptomic profile of ECOs |
Title | Global gene expression profile dataset (microarray) for stem cell derived cholangiocytes and primary biliary tissue |
Description | Micro-array dataset for global gene expression in undifferentiated stem cells, stem cell derived hepatoblasts, stem cell derived cholangiocytes and primary biliary tissue (human bile duct). |
Type Of Material | Database/Collection of data |
Year Produced | 2015 |
Provided To Others? | Yes |
Impact | 1. This dataset provides the first micro-array dataset on the gene expression profile of healhy freshly isolated human biliary tissue (bile duct). This resource will prove very useful for other groups working on biliary development,physiology and pathophysiology 2. This dataset includes the full transcriptional profile of our stem cell derived cholangiocytes, providing a point of reference for other teams focusing on the generation of stem-cell derived cholangiocytes |
URL | https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-2965/ |
Description | Collaboration with Alessandro Bertero on the study OPTiKD: an inducible gene knockdown system to study human development using pluripotent stem cells. |
Organisation | University of Cambridge |
Department | Department of Surgery |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We provided hIPSC-derived cholangiocytes as a platform to test the OPTiKD system |
Collaborator Contribution | Generation and optimization of the OPTiKD platfrom |
Impact | 1. Manuscript in submission in Nature Cell Biology 2. Poster in ISSCR 2015: 2. Bertero A*, Pawlowski M*, Ortmann D, Cardoso de Brito M, Giacomelli E, Sampaziotis F, Hannan NRF, Brown S, Kotter M#, Vallier L#. OPTiKD: an inducible gene knockdown system to study human development using pluripotent stem cells. |
Start Year | 2015 |
Description | Collaboration with Andrew Fisher (University of Newcastle) |
Organisation | University of Newcastle |
Country | Australia |
Sector | Academic/University |
PI Contribution | Isolation of lung tissue and infection with SARS-CoV-2 Design of experiment Provision of UDCA and reagents to be added in the perfusate |
Collaborator Contribution | Provision and ex-vivo perfusion of human lungs Also contributed to designing the experiment |
Impact | Multidisciplinary Transplant surgery, Infectious Diseases 2 papers 1 in revision, 1 published (Meng et al., NAture, 2022) |
Start Year | 2021 |
Description | Collaboration with Athina Markaki and Alex Justin (University of Cambridge, Department of Engineering) for the generation of bio-engineered bile ducts |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provided the cells (cholangiocytes) for seeding on appropriate scaffolds |
Collaborator Contribution | Developed a novel method for the fabrication of cast densified collagen scaffolds |
Impact | This is a multidisciplinary collaboration between the departments of Surgery, Engineering and the Cambridge Stem Cell Institute This collaboration has contributed to a manuscript currently in revision in Nature Medicine This collaboration has resulted in a joint grant application (Rosetrees Trust) for further funding (Co-applicants: Vallier, Markaki, Saeb-Parsy, Sampaziotis, Justin) |
Start Year | 2016 |
Description | Collaboration with CITIID (Steve Baker, Gordon Dougan, Ravi Gupta, Nicholas Matheson, Paul Lehner) |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provision of cholangiocyte organoids for infection with SARS-CoV-2 |
Collaborator Contribution | Provision of SARS-CoV-2 virus, primers to measure virus, antibodies, fluorescent spike protein, HEK cell lines, training in infection |
Impact | 2 papers 1 submitted - in revision 1 published in Nature (see publications, Meng et al, Nature, 2022) |
Start Year | 2021 |
Description | Collaboration with Ed Godfrey and Sara Upponi (Addenbrooke's hospital, department of Radiology) for MRI imaging (reporting) of animals transplanted with bio-engineered bile ducts |
Organisation | Addenbrooke's Hospital |
Department | Department of Oncology |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | Provided the transplanted animals for imaging. The MRI scans were performed by Steve Sawiak (department of Clinical Neurosciences) and reported by Ed Godfrey and Sara Upponi |
Collaborator Contribution | Reported the MRI scans |
Impact | This is a multidisciplinary collaboration between the departtments of Surgery, Radiology and the Cambridge Stem Cell Institute This collaboration contributed to a manuscript currently in revision in Nature Medicine |
Start Year | 2016 |
Description | Collaboration with Ingrid Simonic (Cambridge Genomic Services) for karyotyping of cholangiocyte organoids |
Organisation | University of Cambridge |
Department | Cambridge Genomic Services |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provided cells for karyotyping |
Collaborator Contribution | Karyotyping |
Impact | This collaboration contributed to a manuscript currently in revision in Nature Medicine |
Start Year | 2016 |
Description | Collaboration with Michael Trauner (University of Vienna) |
Organisation | University of Vienna |
Country | Austria |
Sector | Academic/University |
PI Contribution | Training members of the Trauner Lab to grow organoids Contribution to in vitro testing of new drugs for cholangiopathies on cholangiocyte organoids |
Collaborator Contribution | In vivo experiments in mice |
Impact | Part of a multidisciplinary collaboration Outputs Short term EASL fellowship for Claudia Fuchs to visit Cambridge (Trauner lab) Paper submission (in revision) |
Start Year | 2021 |
Description | Collaboration with Université catholique de Louvain - Prof Etienne Sokal |
Organisation | Catholic University of Louvain |
Country | Belgium |
Sector | Academic/University |
PI Contribution | Development of biliary atresia organoids |
Collaborator Contribution | Tissue provision for organoid development |
Impact | This collaboration has just started - no outputs in terms of publications or presentations yet |
Start Year | 2019 |
Description | Collaboration with the University of Oslo and the Norwegian PSC Research Center (NoPSC) |
Organisation | University of Oslo |
Department | Department of Gastroenterology and Hepatology |
Country | Norway |
Sector | Academic/University |
PI Contribution | We have tested a novel risk locus for PSC in hIPSC-derived cholangiocytes, demonstrating its expression in biliary tissue |
Collaborator Contribution | They have identified the risk locus and tested its expression in other platforms such as mice |
Impact | 1. Abstract accepted in ECCO 2016 meeting 2. Paper in submission in Nature Genetics |
Start Year | 2015 |
Description | Collaboration with the Wellcome Trust Sanger Institute for transcriptomic analyses |
Organisation | The Wellcome Trust Sanger Institute |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Provided samples (RNA) for transcriptomic analyses |
Collaborator Contribution | Performed the transcriptomic analyses |
Impact | Publication in Nature Biotechnology |
Start Year | 2014 |
Description | Collaboration with the department of surgery (Kourosh Saeb-Parsy, Olivia Tysoe) to assess the immunogenicity of primary extrahepatic cholangiocyte organoids |
Organisation | University of Cambridge |
Department | Department of Applied Mathematics and Theoretical Physics (DAMTP) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Generated and provided extrahepatic cholangiocyte organoids |
Collaborator Contribution | Generation of humanized mice (immune compromised mice reconstituted with a human immune system) Transplantation of organoids in these mice Assessment of immune response |
Impact | No outputs yet |
Start Year | 2016 |
Description | Collaboration with the department of surgery for cell transplantation in animals and collection of human bile duct samples from rejected liver grafts |
Organisation | University of Cambridge |
Department | Department of Surgery |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | 2014 - Provided stem cell derived cholangiocytes for transplantation in immunocompromised mice. Processed the bile duct samples, extracted RNA and performed genome - wide analyses comparing the transcriptome of primary human bile ducts with that of stem cell deribed cholangiocytes generated by our protocol. The results of our genome-wide analysis are uploaded in the Sanger Institute server, providing a resource that can be accessed by multiple groups working on biliary physiology and disease 2015 - provided bio-engineered tissue for gallbladder reconstruction - experiments successful 2016 - provided bio-engineered bile ducts for transplantation in mice - experiments successful |
Collaborator Contribution | Provided the mice for transplantation Provided human bile duct samples Obtained the necessary ethics approval Obtained informed consent from the donors' families for the use of human bile duct samples for research purposes Transplanted bio-engineered tissue and organs |
Impact | We have demonstrated engraftment and proliferation of our cells in mice. We have demonstrated a significant overlap in the transcriptome of stem cell derived cholangiocytes generated with our protocol and primary biliary tissue, validating our biliary differentiation protocol. These results contributed to a first author publication in Nature Biotechnology (please see publication list) More recently we have demonstrated successful transplantation of bioengineered organs These results contributed to a manuscript currently in revision in Nature Medicine and a grant application to the Rosetrees Trust for further funding |
Start Year | 2014 |
Title | IN VITRO PRODUCTION OF CHOLANGIOCYTES |
Description | This invention relates to the efficient generation of cholangiocyte progenitor (CP) cells. Foregut stem cells (FSCs) are cultured in a hepatic induction medium comprising bone morphogenetic protein (BMP) and a TGFß signalling inhibitor to produce a population of hepatoblasts. The hepatoblasts are then cultured in a biliary induction medium comprising fibroblast growth factor (FGF), retinoic acid and a TGFß ligand to produce a population of cholangiocyte progenitors (CPs). The cholangiocyte progenitors (CPs) may be matured into cholangiocyte-like cells (CLCs) that display functional properties of Common Bile Duct (CBD) cholangiocytes. Methods, kits, cell populations and uses of these cell populations are provided. |
IP Reference | WO2016207621 |
Protection | Patent granted |
Year Protection Granted | 2016 |
Licensed | Yes |
Impact | One of the first protocols for the generation of stem cell cholangiocytes Novel platform for drug validation resulting in the identification of a novel therapeutic candidate for Cystic Fibrosis Liver disease Novel disease modeling platform reproducing the phenotype of Cystic Fibrosis, Polycystic Liver and Kidney Disease and Alagille Syndrome in vitro |
Title | METHODS OF EXPANDING CHOLANGIOCYTES |
Description | This applications describes a novel method for isolating and expanding cholangiocyte organoids, which can subsequently be used for tissue engineering or transplantation and regenerative medicine applications |
IP Reference | GB1709704.9 |
Protection | Patent application published |
Year Protection Granted | 2017 |
Licensed | No |
Impact | Publication - Sampaziotis et al, Nature Medicine, 2017. |
Company Name | BILITECH LTD |
Description | Bilitech is a start-up biotechnology company focusing on the generation and clinical translation of bioengineered bile ducts |
Year Established | 2017 |
Impact | Innovate UK feasibility award Cambridge Enterprise Fast 50 award |
Description | AASLD 2016 Conference - poster presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation on the first biliary reconstruction using bioengineered biliary tissue (Presidential distinction) The meeting was attended by international experts in hepatology and basic science, industry partners and received broad media coverage |
Year(s) Of Engagement Activity | 2016 |
Description | AASLD Hepatology Conference (San Francisco, California) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I presented my work as an oral presentation in the international American Association for the Study of Liver Disease meeting in California. The talk was received enthusiastically by the audience and prompted several requests for future collaborations. |
Year(s) Of Engagement Activity | 2015 |
URL | http://onlinelibrary.wiley.com/doi/10.1002/hep.28160/full |
Description | BASL 2016 Poster presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | BASL poster presentation on the generation of bioengineered biliary tissue The meeting was attended by national and international experts in the field (hepatology), industry partners and received media coverage My poster was awarded a distinction |
Year(s) Of Engagement Activity | 2016 |
Description | BTS Conference 2017 - Medawar Medal presentation and award |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation of my work on the generation and transplantation of a bioengineered bile duct as part of the Medawar Medal award The meeting was attended by national and international experts in the field of transplantation, hepatology, nephrology and cardiology; transplant coordinators, specialist nurses, patient groups, industry partners and patient group representatives and received broad press coverage |
Year(s) Of Engagement Activity | 2017 |
Description | EASL oral presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation on the generation of bioengineered biliary tissue, in the European Liver Meeting in Barcelona. The meeting was attended by international leading scientists and clinicians in the field, industry partners and received press coverage |
Year(s) Of Engagement Activity | 2016 |
Description | EASL talk - Biliary organoids as tools for studying cholangiocyte biology: Cookbook for the inexperienced |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk on the various applications of biliary organoids developed during this award |
Year(s) Of Engagement Activity | 2019 |
Description | Hellenic Medical Society talk (London) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | 70 clinicians attended the talk, which was followed by questions and disussion afterwards. There was significant interest with many requests for further information and copies of the research paper |
Year(s) Of Engagement Activity | 2015 |
Description | Interview by Sparks - published online |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Summary of my research in lay terms provided in the form of an interview organized by one of my funding bodies (Sparks). The interview was published online. |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.sparks.org.uk/a-talk-with-dr-fotios-sampaziotis/ |
Description | Interview for BBC Cambridgeshire |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview with BBC Cambridgeshire describing our work on the generation of bioengineered bile ducts |
Year(s) Of Engagement Activity | 2017 |
Description | Interview on the Naked scientists radio show |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Interview describing the impact of our work on the generation of bioengineered bile ducts. |
Year(s) Of Engagement Activity | 2017 |
Description | Interview with Sparks Charity |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | An interview with Sparks charity about my current work which was posted online in the charity's website and prompted further oureach events including participation in 'the Sparks Breakfast meetings' event |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.sparks.org.uk/a-talk-with-dr-fotios-sampaziotis/ |
Description | Patient Group Workshop - Ask the experts (Support PSC UK group) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Explaining our research and future outlooks to PSC patients |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.youtube.com/watch?v=QGTVCONg_Ck |
Description | Podcast |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Podcast outlining the use of organoids for organ regeneration |
Year(s) Of Engagement Activity | 2021 |
URL | https://podcasts.apple.com/us/podcast/lab-grown-organoids-and-regenerative-medicine-with/id135807974... |
Description | Press Release - MRC |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Simultaneous press release by the Sanger Institute, University of Cambridge, Sparks and ACT which was picked up and disseminated by 3 news outlets (MNT, Medical Xpress, Today Topics). As a result 2 groups have already requested collaborations and the press releases prompted a report on our work in Nature Reviews Gastroenterolgy and Hepatology |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.mrc.ac.uk/news/browse/scientists-grow-mini-bile-ducts-to-help-discovery-of-new-drugs/ |
Description | Press Release - Wellcome Trust Sanger Institute |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Simultaneous press release by the Sanger Institute, University of Cambridge, Sparks and ACT which was picked up and disseminated by 3 news outlets (MNT, Medical Xpress, Today Topics). As a result 2 groups have already requested collaborations and the press releases prompted a report on our work in Nature Reviews Gastroenterolgy and Hepatology |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.sanger.ac.uk/news/view/2015-07-13-scientists-create-mini-liver-segments-for-drug-discover... |
Description | Press release - Sparks charity |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Simultaneous press release by the University of Cambridge, Sparks, MRC, Wellcome Trust Sanger Institute. Outcomes as already described |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.sparks.org.uk/pioneering-medical-research-breakthrough/ |
Description | Press release - University of Cambridge |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Simultaneous press release by the Sanger Institute, University of Cambridge, Sparks and ACT which was picked up and disseminated by 3 news outlets (MNT, Medical Xpress, Today Topics). As a result 2 groups have already requested collaborations and the press releases prompted a report on our work in Nature Reviews Gastroenterolgy and Hepatology |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.cam.ac.uk/research/news/mini-bile-ducts-help-identify-new-drugs-that-could-prevent-the-n... |
Description | Report in Nature Reviews Gastroenterology & Hepatology |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A request for communication about our work by the editor of Nature Reviews Gastroenterology and Hepatology, led to a report on our work in the journal. This 'research highlight' section has contributed significantly to disseminating our work to other disciplines outside our immediate field and has already prompted 2 requests for collaborations |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.nature.com/nrgastro/journal/v12/n9/full/nrgastro.2015.129.html |
Description | TEDx Talk in the University of West Attica |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Invited TEDx talk entitled Tissue Regeneration - A ticket to improving life? |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.ted.com/tedx/events/37361 |
Description | Talk in the 4th congress on gene therapy and regenerative medicine: Translational applications of cholangiocyte organoids |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Overview of the translational work on biliary organoids performed during this award |
Year(s) Of Engagement Activity | 2019 |
Description | UEG - Invited speaker |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation of an overview of my work on clinical applications of in vitro propagated cholangiocytes (invited speaker) The meeting was attended by international experts in the fields of hepatology and gastroenterology, basic scientists, industry partners and received press coverage The talks were streamed online |
Year(s) Of Engagement Activity | 2016 |