End stage liver disease (ESLD) is an irreversible condition that leads to the eventual failure of the liver. It may be the final stage of many liver diseases, for example, viral hepatitis, autoimmune hepatic disorders, fatty liver disease, drug induced liver injury, and hepatocellular carcinoma, with extremely poor prognosis. The incidence of ESLD is increasing worldwide[1
], and current optimal treatment for ESLD is orthotopic liver transplantation[2
]. However limited availability of donor livers and immunological incompatibilities are two major obstacles to its routine deployment[3
]. This highlights the important need for alternative therapeutic strategies. Researchers have proposed that stem cell biology could provide a scalable answer for the treatment of ESLD, providing cells for transplant and/or cell sources for studying liver disorders and identifying novel treatments.
Cell-based therapy requires the use of cells to replace or facilitate the repair of damaged tissue. Candidate cells for this approach include bipotential, multipotent, pluripotent cells, and primary hepatocytes. Pluripotent stem cells (PSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), possess the ability to self renew and differentiate into all somatic cells, offering unlimited potential and are not restricted by donor tissue supply.
hESCs are derived from the inner cell mass of the human blastocyst, and can differentiate into all three primary germ layers[4
]. Human iPSCs are produced by forced expression of specific stem cell genes[5
]. In recent years, researchers have developed robust procedures to generate functional hepatocyte-like cells (HLCs) from both PSC populations[6-8
]. However, it is notable that PSC strategies have not yielded, as yet, a cell type that appropriately contributes to tissue homeostasis as cell transplantation frequently results in tumour formation[9,10
]. As a result, scalable cell-based therapies from PSCs are likely to be longer-term strategies which require significant refinement.
Extra-corporeal support has been proposed as a mid-term strategy, in particular bio-artificial livers, to treat human liver disease. Bio-artificial livers (BALs) are designed to filter and biotransform toxic substances, and have been used successfully to bridge patients to transplant or treat acute liver failure. Research demonstrates that BALs can reduce mortality in acute liver failure compared with traditional standard medical therapy[11,12
], but the application has been severely limited by the poor availability of functional human hepatocytes. By employing PSC technology, it may now be possible to produce humanised BAL devices at reasonable cost.
In addition to their important role in the clinic, human hepatocytes have a critical part to play in the drug discovery process. Many candidate compounds fail at late stage or even after approval due to unanticipated toxicity. In routine drug discovery, the pharmaceutical industry deploys the tumor-derived cells and primary hepatocytes to screen compounds. While these models are useful, they do not always extrapolate to human biology and exhibit poor lifespan and variable metabolic activity. PSCs-derived hepatocytes have the potential to overcome these problems. Advances in stem cell biology and reprograming have allowed the development of novel models which have the potential to provide another level of understanding behind the pathophysiology of liver diseases. iPSC modelling also provides us with potential system to better understand the influence of gene polymorphisms.
Human PSCs derived HLCs show great promise for research and clinical applications including cell-based therapies, drug development, and disease modeling. This review gives an overview of human hepatic differentiation from PSCs and their potential application in modern medicine.