The development of 3-dimensional implantable liver organoids

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Regenerative Medicine

Abstract

Liver disease is the 5th most common cause of death in the UK. 16,087 people in the UK died from liver disease in 2008, a 4.5% increase since 2007 and trends are rising. Liver disease kills more people than diabetes and road deaths combined. The only curative option for end-stage cirrhosis and acute liver failure is liver transplantation, however organ availability cannot meet demand and many patients die waiting for an organ. Those who undergo transplantation require lifelong treatment with increased risks of infection, cancer, kidney and heart disease. Thus, there is a clear need to identify alternatives to liver transplantation. Recent studies have shown that human cells can small fragments of liver like tissue. While providing proof of concept, the tissue is very small and lacks key liver functions. To address this we have assembled a team with complementary expertise to reliably produce human liver tissue with clinically relevant function.

Technical Summary

Liver disease is the 5th most common cause of death in the UK. 16,087 people in the UK died from liver disease in 2008, a 4.5% increase since 2007 and trends are rising. Liver disease kills more people than diabetes and road deaths combined (REF: Office for National Statistics: Health Service Quarterly, Winter 2008, No. 40 p59-60). The only curative option for end-stage cirrhosis and acute liver failure is liver transplantation, however organ availability cannot meet demand and many patients die waiting for an organ. Those who undergo transplantation require lifelong immunosuppression with concomitant risks of infection, cancer, renal and cardiovascular disease. Thus, there is a clear imperative to identify alternatives to liver transplantation. Recent studies have shown human pluripotent stem cells (hPSC) co-cultured with MSCs and endothelial cells can form primitive liver organoids (Takebe et al. Nature 2013). While providing proof of concept the in vitro derived spheroids are tiny and lack a functional biliary system, requiring transformative innovation before they can be used clinically. To deliver this we have assembled a team with complementary expertise in the production and use of stem cell derived hepatocyte and cholangiocytes-like cells, hepatocyte niche construction, three-dimensional scaffold production and in vivo modelling. This collaborative group includes scientists and clinicians with experience in human cell production, GMP cell production and clinical cell therapy for liver disease. This group is ideally placed to translate these pre-clinical observations into a therapy for patients with liver failure or metabolic liver diseases, and particularly the use of liver buds derived from genetically corrected iPS cells in the case of liver disease caused by single gene defects.

Planned Impact

This project will develop the technology needed to help advance the treatment of human liver disease by providing implantable devices for liver support. We envisage clinical utility in 4 settings:
(a) Where acute liver injury had occurred (drug-induced or post-hepatectomy) and this liver support would support the patient until endogenous repair had occurred,
(b) In acute on chronic liver failure where the patient has been listed for transplantation but no suitable organ is immediately available- the aim would be to stabilise and support the patient until a suitable donor organ is available
(c) As rescue therapy in paediatric cases of inborn errors of liver metabolism where the lack of specific proteins in the patient hepatocytes can lead to multiple organ failure.
(d) The ability to model human disease 'in a dish' has revolutionary potential for new and safer drug design to treat liver disease and tissue regeneration.
The changeable genetic element within our system will allow for the tissue to be tailor-made for the recipient, obviating the need for immunosuppressive drugs (and their side effects). This type of disruptive technology will bolster economic development within the UK and maintain our position as a world leader in our respective scientific fields. Such improvements will have significant benefits in terms of direct and indirect healthcare costs, social and welfare costs. In addition, by addressing an unmet medical need, the project has a great potential for wealth creation for the UK. To develop the impacts we shall engage:
(i) Clinical practitioners and transplant surgeons
The consortium has strong clinical focus. Engagement with the relevant clinical practitioners and transplant surgeons has already been established. SJ Forbes, A Dhawan and PN Newsome are clinicians within 3 large UK liver transplant units covering both adult and paediatric liver patients.
(ii) Cell based modeling to develop safer and new medicines
The consortium has built up a strong relationship with industry and is well positioned to deliver novel models for application. The benefits for the industry have the potential to be realised within only a few months of completion of the project. Academic research groups could also utilise the technology within a similar time frame.
(iii) Government / Regulatory Authorities
The introduction of new treatments for liver disease or screening models will lead to the development of novel medicines, which will be managed in consultation with regulatory authorities that oversee drug safety, efficacy and cost. We have engaged with the Cell Therapy Catapult who see the merit of our application and have provided a letter of support.

Publications

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Alwahsh SM (2018) Liver cell therapy: is this the end of the beginning? in Cellular and molecular life sciences : CMLS

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Cameron K (2015) Serum-Free Directed Differentiation of Human Embryonic Stem Cells to Hepatocytes. in Methods in molecular biology (Clifton, N.J.)

 
Title Front cover - Best of Stem Cell Reports 2015 
Description Front cover - Best of Stem Cell Reports 2015 
Type Of Art Artwork 
Year Produced 2015 
Impact Communication with peers 
URL http://onlinedigeditions.com/publication/frame.php?i=260435&p=&pn=&ver=html5
 
Title Frontispiece 
Description Advanced Healthcare Materials Frontispiece 
Type Of Art Artwork 
Year Produced 2015 
Impact Communication with peers 
URL http://onlinelibrary.wiley.com/doi/10.1002/adhm.201570072/abstract
 
Title Lab Tube TV interview 
Description Interview with lab tube TV 
Type Of Art Film/Video/Animation 
Year Produced 2015 
Impact 659 VIEWS 
URL https://www.labtube.tv/video/labtube-meets-david-hay-mrc-centre-for-regenerative-medicine
 
Description Exploiting hepatocyte and endothelial cell interactions for the development of scalable human liver tissue.
Amount £372,333 (GBP)
Funding ID TCS/16/37 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 08/2017 
End 02/2020
 
Description Innovate UK
Amount £831,782 (GBP)
Funding ID 93592-562428 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 10/2017 
End 09/2019
 
Title Modelling non-alcoholic fatty liver disease in human hepatocyte-like cells. 
Description Modelling non-alcoholic fatty liver disease in human hepatocyte-like cells 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2018 
Provided To Others? Yes  
Impact Transferred to industry non-exclusively 
URL https://www.ncbi.nlm.nih.gov/pubmed/29786565
 
Title Stem cell differentiation bioinformatics 
Description Comparing gene expression of adult human hepatocytes to stem cell derived hepatocytes 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Other researchers around the world using this system as reference - Godoy et al Archives of Toxicol 2016, Mallanna et al 2016 Stem Cell Reports 
URL https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3994/
 
Description HBV project 
Organisation University of North Carolina at Chapel Hill
Department Department of Microbiology and Immunology
Country United States 
Sector Academic/University 
PI Contribution Provision of stem cell derived hepatocytes
Collaborator Contribution In vivo transplant of stem cell derived hepatocytes and HBV infection
Impact None as yet. The project is on going,
Start Year 2015
 
Description HCC Models in Stem Cell Derived Hepatocytes 
Organisation Brunel University London
Department Department of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided training to Michael Thermis' lab to produce stem cell derived hepatocytes from hESC and IPSCs for modelling human HCC 'in a dish'
Collaborator Contribution Michael's team will make the HCC model at Brunel
Impact none as yet. We are in the process of preparing a phase II application to the NC3Rs.
Start Year 2016
 
Description Hepatocyte Bioinformatics 
Organisation Leibniz Association
Country Germany 
Sector Public 
PI Contribution Provison of differing hepatocytes populations for analysis by gene array
Collaborator Contribution Expertise in gene arraying and bioinformatics
Impact 2 manuscripts published - see publications
Start Year 2014
 
Description Lamin driected differentiation 
Organisation Biolamina
Country Sweden 
Sector Charity/Non Profit 
PI Contribution The collaboration has allowed us to produce better stem cell derived hepatocytes. We have protected our intellectual property with Biolamina - LCTI 200041USP1
Collaborator Contribution Provision of discounted recombinant laminins for use.
Impact Recombinant Laminins Drive the Differentiation and Self-Organization of hESC-Derived Hepatocytes. Cameron K, Tan R, Schmidt-Heck W, Campos G, Lyall MJ, Wang Y, Lucendo-Villarin B, Szkolnicka D, Bates N, Kimber SJ, Hengstler JG, Godoy P, Forbes SJ, Hay DC. Stem Cell Reports. 2015 Dec 8;5(6):1250-62. doi: 10.1016/j.stemcr.2015.10.016. Epub 2015 Nov 25. PMID: 26626180 Patent application - METHODS FOR PRODUCING HEPATOCYTES - LCTI 200041USP1.
Start Year 2014
 
Description Liver on a chip commercilisation 
Organisation Stemnovate Limited
PI Contribution Stemnovate have non exclusively licensed our stem cell derived hepatocyte technology. We will provide know how and training.
Collaborator Contribution Financial contribution to a PhD programme - *BBSRC EASTBIO* Modelling foetal liver development and disruption using pluripotent stem cells (iCase)
Impact In the process of interviewing
Start Year 2017
 
Description iHep and iPSC Hep collaboration 
Organisation Chinese Academy of Sciences
Department Institute of Biochemistry and Cell Biology
Country China 
Sector Academic/University 
PI Contribution Transfer of stem cell technology from UK to China
Collaborator Contribution Validation of our stem cell differentiation procedures
Impact Paper in preparation, to be submitted by Q2 2016
Start Year 2015
 
Title METHODS FOR PRODUCING HEPATOCYTES 
Description Disclosed herein are methods for producing hepatocytes with more natural properties and more differentiated function. Generally, those methods comprise: plating pluripotent human stem cells on a cell culture substrate comprising (i) a first laminin which is laminin-521 and (ii) a second laminin selected from the group consisting of laminin-111 and laminin-221, wherein the laminin-521 and the second laminin are each either an intact protein or a protein fragment; and culturing the pluripotent human stem cells to obtain the hepatocytes. The resulting hepatocytes exhibit efficient hepatocyte specification, organisation, maturation and significant improvements in cell function and stability. It is believed that the laminins suppress inappropriate gene regulatory networks controlling cell proliferation, cell migration, stem cell self-renewal, and colon and fibroblast specification. The stem cells themselves should be research and GMP grade. 
IP Reference LCTI 200041USP1 
Protection Patent application published
Year Protection Granted
Licensed Commercial In Confidence
Impact Numerous publications (detailed before)reproduced our press release.
 
Description 50 Ideas to Change the World: Liver success holds promise of 3D organ printing 
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 Industry/Business
Results and Impact lNew livers, hearts, kidneys: the idea of one day being able to 3D print replacement human organs has been a dream for scientists working in the field of regenerative medicine. The ability to print whole organs is still in the distance but work is under way across multiple laboratories to print tissues of the liver, the most regenerative organ in the body.
Year(s) Of Engagement Activity 2018
URL https://www.ft.com/content/67e3ab88-f56f-11e7-a4c9-bbdefa4f210b
 
Description Fresh hope for transplant patients after Scots breakthrough 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Newspaper article featuring our transplanted human liver tissue derived from pluripotent stem cells
Year(s) Of Engagement Activity 2018
URL https://www.pressreader.com/uk/scottish-daily-mail/20180828/281977493484972
 
Description SWI Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact An evening lecture to the Scottish Women's Institute
Year(s) Of Engagement Activity 2018
URL https://allevents.in/midlothian/meeting-making-liver-tissue-from-stem-cells-a-talk-from-professor-da...
 
Description Scientists find that smoking harms livers of unborn babies 
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 Two radio interviews
Year(s) Of Engagement Activity 2017
URL https://www.bbc.co.uk/news/uk-scotland-40084844
 
Description Stem cell 'advance' hailed by scientists 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Patented procedure to generate hepatocytes from stem cells - http://www.freepatentsonline.com/y2017/0121686.html
Year(s) Of Engagement Activity 2015
URL https://www.pressreader.com/uk/the-herald/20151126/281908772057947/TextView