Manipulation of niche signals to advance cell therapies for liver disease

肝病是英国第五大常见的死亡原因，其发病率正在迅速增加。目前治疗肝衰竭的唯一方法是用一个新的器官替换衰竭的器官--这一过程被称为肝移植。不幸的是，我们根本没有足够的捐赠器官来满足需要新肝脏的患者激增的需求。在过去的几年里，一种名为“诱导多能性”（iPS）的新技术已经出现，作为一个潜在的解决方案。在这项技术中，从患者身上获得的皮肤细胞可以在培养皿中重新编程，然后转化为肝细胞，然后再移植回同一患者体内。通过这种方式，人们相信可以避免完整的器官移植，此外也不需要有害的免疫抑制药物。第一波诱导多能干细胞产品虽然前景光明，但也说明了几个问题。主要的一个原因是，培养皿中产生的细胞似乎不够成熟，如果用在病人身上，就不足以产生治愈效果。事实上，到目前为止产生的细胞看起来更像胎儿或祖细胞。因此，为了将这些细胞用于临床应用，我们目前的理解需要取得重大进展，使成熟的最后步骤和随后的移植成功。许多研究人员认为，细胞（“种子”）周围的生态位（“土壤”）对它们的行为有着深远的影响。因此，了解土壤可能是克服我们在种子方面遇到的问题的关键。通过了解生态位如何影响发育中，成人和患病肝脏中的祖细胞（婴儿）和成人肝细胞，我将能够设计新的策略来克服这些问题。因此，我的总体目标是利用这些新知识开发基于细胞的治疗方法，用于治疗严重的和无法治疗的肝病。

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.