Manipulation of niche signals to advance cell therapies for liver disease

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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.