INSERM UMR-S972, Paul Brousse Hospital, Villejuif, F-94807, France.
Curr Gene Ther. 2013 Apr;13(2):120-32. doi: 10.2174/1566523211313020006.
The liver is affected by many types of diseases, including metabolic disorders and acute liver failure. Orthotopic liver transplantation (OLT) is currently the only effective treatment for life-threatening liver diseases but transplantation of allogeneic hepatocytes has now become an alternative as it is less invasive than OLT and can be performed repeatedly. However, this approach is hampered by the shortage of organ donors, and the problems related to the isolation of high quality adult hepatocytes, their cryopreservation and their absence of proliferation in culture. Liver is also a key organ to assess the pharmacokinetics and toxicology of xenobiotics and for drug discovery, but appropriate cell culture systems are lacking. All these problems have highlighted the need to explore other sources of cells such as stem cells that could be isolated, expanded to yield sufficiently large populations and then induced to differentiate into functional hepatocytes. The presence of a niche of "facultative" progenitor and stem cells in the normal liver has recently been confirmed but they display no telomerase activity. The recent discovery that human induced pluripotent stem cells can be generated from somatic cells has renewed hopes for regenerative medicine and in vitro disease modelling, as these cells are easily accessible. We review here the present progresses, limits and challenges for the generation of functional hepatocytes from human pluripotent stem cells in view of their potential use in regenerative medicine and drug discovery.
肝脏会受到多种疾病的影响，包括代谢紊乱和急性肝衰竭。目前，原位肝移植（OLT）是治疗危及生命的肝脏疾病的唯一有效方法，但同种异体肝细胞移植现在已成为一种替代方法，因为它比 OLT 侵入性更小，并且可以重复进行。然而，这种方法受到器官捐献者短缺的限制，以及与高质量成人肝细胞的分离、其冷冻保存以及在培养中缺乏增殖相关的问题。肝脏也是评估外源性物质药代动力学和毒理学以及药物发现的关键器官，但缺乏适当的细胞培养系统。所有这些问题都突出表明需要探索其他细胞来源，如干细胞，可以对其进行分离、扩增以产生足够大的群体，然后诱导其分化为功能性肝细胞。最近已经证实，正常肝脏中存在“兼性”祖细胞和干细胞的龛位，但它们没有端粒酶活性。最近发现，体细胞可以被诱导分化成多能干细胞，这为再生医学和体外疾病建模带来了新的希望，因为这些细胞很容易获得。我们在此回顾了从人类多能干细胞生成功能性肝细胞的当前进展、限制和挑战，以期在再生医学和药物发现中得到应用。
