Autologous macrophage therapy promotes stem cell-mediated liver regeneration:a novel therapy for end-stage liver disease

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

Abstract

Liver disease is the 5th commonest cause of death in the UK and deaths from cirrhosis are rapidly rising. Currently the only curative option for end-stage liver disease is liver transplantation and this is limited in availability due to a lack of suitable donor livers. As a result of this, many patients die whilst waiting for a donor organ, hence new therapeutic strategies for patients with end-stage liver disease are urgently required. Cell therapy using bone marrow has been tested in rodents and has shown to significantly reduce liver scarring, which is a precursor to cirrhosis. We have found that in addition this effect bone marrow therapy stimulates the livers own stem cells to start dividing and regenerate the liver. We have identified the cell type within the bone marrow that is responsible for this effect termed macrophages. This is exciting as these cells can be isolated from a patient?s blood in an immature form in large numbers and matured in the laboratory effectively.
Here, we describe a novel approach to the treatment of liver cirrhosis using blood derived cells which have been matured outwith the body into macrophages prior to re-injection into the blood stream. This therapy is simple to administer and has the potential to reduce liver scarring and promote liver regeneration. The pre-clinical studies are designed to test the safety and effectiveness of this technique in a wide range of liver disease models- if they are effective they will be directly translated into patients in a clinical pilot study.

Technical Summary

Liver disease is the 5th commonest cause of death in the UK and deaths from cirrhosis are rapidly rising. Currently the only curative option for end-stage liver disease is liver transplantation and this is limited in availability due to a lack of suitable donor organs. Many patients die whilst waiting for a donor organ, hence new therapeutic strategies for patients with end-stage chronic liver disease are urgently required.

Autologous bone marrow (BM) cell therapy has been tested in rodent models and has been shown to significantly reduce liver fibrosis. Interestingly, from our studies we have found that in addition to the anti-fibrogenic effect, BM cell therapy also activates the adult liver?s stem cell pool, producing a classic liver progenitor cell (LPC) reaction in the host. This is of considerable interest, as LPCs are known to facilitate liver regeneration in situations in which adult hepatocytes are unable to. Our studies indicate that is the BM-derived macrophages that are the effector cells in this response. Furthermore, we have recently found that na?ve macrophages, matured ex vivo in low adherence culture conditions are as effective as whole BM in eliciting both anti-fibrotic and pro-regenerative effect. Thus macrophage therapy may elicit the dual beneficial effects of reducing fibrosis and regenerating liver from its endogenous stem cell pool. This proposal aims to develop a GMP-compatible system for maturation of monocytes into macrophages using MCSF and low adhesion culture conditions. We will then define the optimal form of LPC-promoting macrophage therapy and rigorously test its safety in a comprehensive series of animal models and explore the mechanism by which macrophage therapy promotes LPC mediated liver regeneration. Using this information we will validate the maturation system for human monocytes and test them in vivo in an immunodeficient mouse (NOG) liver injury model. If pre-clinical studies demonstrate that macrophage therapy is safe and effectively promotes liver regeneration then we will have achieved our milestone to allow us to progress to a clinical study. The clinical study will involve using autologous monocytes, matured ex-vivo into macrophages delivered to suitable patients (as determined by our animal models) with liver cirrhosis. Measured outcomes will include markers of liver function, liver regeneration and liver fibrosis.

Publications

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Bird TG (2013) Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. in Proceedings of the National Academy of Sciences of the United States of America

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Boulter L (2013) Differentiation of progenitors in the liver: a matter of local choice. in The Journal of clinical investigation

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Boulter L (2015) WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. in The Journal of clinical investigation

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Campana L (2017) Regression of Liver Fibrosis. in Seminars in liver disease

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Gibbons MA (2011) Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. in American journal of respiratory and critical care medicine

 
Description MRC research training fellowship
Amount £239,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2011 
End 08/2014
 
Description research training fellowship
Amount £263,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 08/2014
 
Description research training fellowship
Amount £271,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 08/2014
 
Description liver fibrosis and regeneration 
Organisation University of Edinburgh
Department MRC Centre for Inflammation Research
Country United Kingdom 
Sector Public 
PI Contribution co-supervision of several joint studentships and clinical training fellowships co-PI on a programme grant
Collaborator Contribution research collaboration resulting in several publications
Impact several papers, research training fellowships, a programme grant and a project grant
Start Year 2006
 
Description liver fibrosis and regeneration 
Organisation University of Edinburgh
Department MRC Centre for Inflammation Research
Country United Kingdom 
Sector Public 
PI Contribution co-supervision of several joint studentships and clinical training fellowships co-PI on a programme grant
Collaborator Contribution research collaboration resulting in several publications
Impact several papers, research training fellowships, a programme grant and a project grant
Start Year 2006
 
Description MRC Research Showcase at the Scottish Parliament 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact MRC Research Showcase at the Scottish Parliament highlighting biomedical research within Scottish Universities funded by the MRC.Professor Hay reported that he will have followup discussions with Miles Briggs MSP about health policy.
Year(s) Of Engagement Activity 2018
URL https://twitter.com/crm_edinburgh/status/1093224653341057025
 
Description RSE Lecture: Innovation in Organ Transplantation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Lecture given at Royal Society of Edinburgh: Innovation in Organ Transplantation
Year(s) Of Engagement Activity 2018
 
Description Regeneration Innovation 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Workshop to encourage and stimulate translation and commercialisation of research from the CRM. Speed networking and an innovation competition were included as acitvities as well as presentations from existing industry collaborations.
Year(s) Of Engagement Activity 2018
 
Description outreach meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Public engagement events and lectures via the stem cell network. Attended typically by over 100 members of public to expalin stem cell science and translational potential.

Hosting Nuffield bursary pupils in lab on regular basis
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011