Developing stem cell therapies for the treatment of inherited and acquired liver disease

Stem cell based approaches are likely to be key in the future development of novel therapies for many diseases ranging from the replacement or repair of organs affected by injury or the effects of ageing through to ways to modify the body's own responses to injury, which can have lasting damaging effects when out of control. This project will underpin a research initiative between the University of Birmingham (UoB) and the Guangzhou Institute of Biomedicine and Health (GIBH) that seeks to develop novel stem cell based therapies. GIBH has a strong international reputation in fundamental stem cell biology, while UoB has unrivalled experience in the development of cell-based therapies and their testing in clinical trials. This initiative will be a model for international research collaboration at the highest level, each institution gaining from the other's expertise and specialist resources to enable delivery of cutting-edge research outcomes with the objective to translate discoveries rapidly into patient benefit.

This pilot project will focus on the development of stem cell-based means to tackle a wide range of liver diseases. Liver disease is a major cause of morbidity and mortality in modern societies. In the UK the prevalence of chronic liver disease is between 0.76-1% and represents the fifth 'big killer' in England & Wales, and is the only disease in the top 5 that is still increasing year-on-year. The majority of this relates to chronic liver damage due to alcohol, viruses or obesity, but also includes liver damage resulting from acute (paracetamol) injury or autoimmune destruction. The situation of liver disease is even more alarming in China. Historically this reflected Hepatitis B infection, although chronic liver disease due to obesity is now rising. In addition, a number of inherited traits impact on liver function resulting in metabolic disorders. For many of these diseases there is no effective treatment, except liver transplantation.

The project will explore how induced pluripotent stem cells (iPSCs) can be utilised in a variety of ways in the treatment of liver diseases. iPSCs can be made from any readily available cells, such as from the skin, and have the potential to be maintained and expanded indefinitely. At the same time iPSCs can be converted into cell types to act as replacements for damaged tissue or into specific cell types with other useful therapeutic properties. GIBH are world leaders in the generation of iPSCs, and will join forces with the UoB team to produce and test two different cell types from them that have relevance in the treatment of liver disease. The first will be liver cells (hepatocytes), which the Birmingham team has expertise in producing f(from human embryonic stem cells) and testing in animal models of liver damage. The second cell type are mesenchymal stromal (or stem) cells (MSCs), which have the ability to dampen the body's own exaggerated inflammatory response to certain injuries, which if left unchecked can itself result in long term damage.

In addition to setting up and sharing protocols for the generation and testing of hepatocytes and MSCs, this project will also lay the groundwork for the establishment of a shared cell 'bank' that will pave the way for more extensive research. In particular, it will act as a resource for a more 'personalised' approach to stem cell-based therapy since iPSCs will be made from a wide range of individuals with different genetic backgrounds, including some who have defined inherited genetic defects that impact upon liver function.

Overall, the proposed project will contribute to the foundation for a joint research laboratory and a stem cell bank between the involved institutions of Birmingham and Guangzhou, and is expected to develop new concepts and therapeutic possibilities that will benefit people from the UK and China.

Liver disease is a major cause of morbidity and mortality in modern societies. An improved outlook for these patients will come about through a better understanding of the disease mechanisms and innovative therapeutic approaches, including stem cell-based therapies.

A major problem in attaining these goals is our inability to produce high quality patient-specific hepatocytes. The generation of induced pluripotent stem cells (iPSCs) by nuclear reprogramming of somatic cells with exogenous transcription factors raises the possibility of creating personalised disease models and cell-based therapies. In this proposal we aim to generate high quality hepatocytes from human iPSCs that we will test in preclinical models of liver injury. In addition, because mesenchymal stem cells (MSCs) have proven therapeutic efficacy in multiple disease models through their immunomodulatory capacity, we will compare the functional characteristics of human iPSC-derived MSCs with primary MSCs from normal individuals and test their therapeutic efficacy in models of liver injury. This proposal will contribute to the foundation for a joint research laboratory and a stem cell bank between the involved institutions of Birmingham and Guangzhou, and is expected to develop new concepts and therapeutic possibilities that will benefit people from the UK and China.

Impact on Knowledge - New information on the generation of iPSCs and their subsequent differentiation to either hepatocytes or mesenchymal stem cells, both of which will be tested for level of functionality through assessment in animal models of liver injury. This knowledge will be disseminated through publication in international journals and as well through channels such as the University of Birmingham Stem Cell Centre, BUSCC, the regional stem cell network, MSCA, and connections with the Guangzhou institute.

Impact on Communication and Engagement - This will be achieved through the auspices of BUSCC and through events held locally in the University and the associated NHS Trust hospitals or in the City of Birmingham at which the public can engage in informed debate about a variety of issues related to stem cell science.

Impact on health and quality of life - Although the research in this project will be pre-clinical in nature, it is expected that some of the studies will form the basis for early stage clinical trials to be conducted in Birmingham. Long-term, the findings from this project should impact initially on a range of liver diseases, and eventually will inform the development of novel therapeutic strategies that can be applied in a variety of organ damage scenarios.

Impact on International Collaboration - The basis of this project is firmly grounded in a developing international collaboration between Birmingham and Guangzhou. It is expected that this will widen as the planned joint centre for stem cell biology and regenerative medicine demonstrates effective operation and real translational outputs.

Impact on People - The project will lead to training of both postdoctoral and technical staff, and will impact on the training of others in the laboratories, including PhD students, in both Birmingham and Guangzhou. The expertise of the applicants, and the new knowledge gained will be of use to several other research groups in the local research environments.

Impact on the Economy - We will continue to contribute to development of the local science infrastructure and in providing skilled researchers needed for academia and industry. The potential impact on health of individuals will have economic benefit, as will the inevitable links with small and medium-sized enterprises that will become involved once the projects move towards the clinical trial stage.