Manipulation of niche signals to advance cell therapies for liver disease

Liver disease is the fifth commonest cause of death in the UK and its incidence is rapidly increasing. Currently the only cure for liver failure is to replace the failing organ with a new one - a procedure known as a liver transplant. Unfortunately we simply do not have enough donor organs to meet the surging demands of patients requiring new livers.
Over the last few years, a new technology named "induced pluripotency" (iPS) has emerged as a potential solution to this problem. In this technique skin cells obtained from a patient can be reprogrammed in a dish and then converted into liver cells before being transplanted back into the same patient. In this way it is believed that a full organ transplant could be avoided and in addition no harmful immuno-suppressant medications would be required.
The first wave of induced pluripotent stem cell products, whilst promising, illustrated several problems. The main one being that cells produced in a dish did not appear mature enough to produce a cure if used in a patient. In fact, cells produced up till now look more like fetal or progenitor cells. Thus, in order to take these cells into clinical application, major advances to our current understanding that allow the final steps of maturation and subsequent transplantation to be successful will be needed. Many researchers believe that the niche ("the soil") surrounding cells ("the seed") has a profound effect upon their behaviour. Understanding the soil therefore may be the key to overcoming problems we have experienced with the seeds. By understanding how the niche influences both progenitor (baby) and adult liver cells in the developing, adult and diseased livers, I will be able to design new strategies to overcome such problems.
My overall aim therefore is to use this new knowledge to develop cell based therapies for serious and otherwise untreatable liver diseases.

My objectives and overall strategy are to understand the mechanisms that regulate maturation, proliferation and survival of hiPSC derived and adult human hepatocytes through:

(1) An understanding of hepatic tissue niches reconstructed using high throughout screening platforms (niche microarrays and small molecules)
(2) An understanding of more complicated 3-Dimensional hepatic niches reconstructed using engineered multi-celluar PEG scaffolds and a small animal bioreactor.

To push towards a therapeutic goal, we will utilise the information gained from sections (1) and (2) with understanding of the abnormal niche created as a result of liver damage, to try and engineer a hybrid "cell - scaffold", which allows transplanted cells to become 'curative' when given to patients.

1. Regenerating damaged tissues and restoring their function is one of the major goals of biomedicine. Diseases that cause tissue degeneration and injury present a huge and ever-increasing clinical burden, in the UK costing the NHS well over £1 bn/year. My research will expedite stem/progenitor cell discoveries, focusing on developing new liver repair/regeneration strategies for patient benefit. I will achieve this by determining how local tissue niche composition, notably extracellular matrix, cytokines and growth factors, direct stem/progenitor cell phenotype, growth and differentiation, by building niche based biomaterial platforms for tissue-specific engraftment and regulation of cell phenotype in vitro and in vivo, and by the discovery of novel targets for promoting endogenous repair. I will utilise high throughput, high content and phenotype screens (including small molecules) to fast track achievement of these key goals.
The engagement with two of the leading stem cell facilities in the world (Harvard & MIT) will strengthen UK standing in international stem cell networks and facilitate participation at a high level in major national and international conferences. Reporting of the scientific discoveries and translational advances in high-impact scientific journals will also contribute prominently to the advancement of the UK as a world-leading 'brand' in tissue regeneration and repair.
2. Novel targets for achieving clinical therapy may also be defined in this research and will therefore become of interest to biotech/pharma. Such outputs will also be pursued by careful consideration of IP generation.