Human hepatocyte transplantation: state of the art. J Intern Med

Paediatric Liver Centre, King's College London School of Medicine at King's College Hospital, UK.
Journal of Internal Medicine (Impact Factor: 6.06). 10/2009; 266(4):339-57. DOI: 10.1111/j.1365-2796.2009.02152.x
Source: PubMed


Hepatocyte transplantation is making its transition from bench to bedside for liver-based metabolic disorders and acute liver failure. Over eighty patients have now been transplanted world wide and the safety of the procedure together with medium-term success has been established. A major limiting factor in the field is the availability of good quality cells as hepatocytes are derived from grafts that are deemed unsuitable for transplantation. Alternative sources of cell, including stem cells may provide a sustainable equivalent to primary hepatocytes. There is also a need to develop techniques that will improve the engraftment, survival and function of transplanted hepatocytes. Such developments may allow hepatocyte transplantation to become an accepted and practical alternative to liver transplantation in the near future.

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    • "Umbilical cord is an available and non-invasive source of stem cells with no ethical concern. Mesenchymal stem cells (MSCs) derived from the human umbilical cord, Wharton's jelly, can be considered as one of the best cell sources for hepatocyte differentiation and transplantation among various therapeutic strategies and stem cells therapy [3] [4] [5] [6] [7]. Wharton's jelly MSCs (WJ-MSCs) have more self-renewal capacity as well as the ability to differentiate into various cell types, including adipocyte, osteocytes, and chondrocytes [8] [9]. "
    [Show abstract] [Hide abstract] ABSTRACT: The research on Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) from the umbilical cord suggests promising therapeutic use for hepatocyte replacement therapy. One of the highly conserved members of the nuclear receptor superfamily in the liver is hepatocyte nuclear factor-4α (HNF4α), involved in hepatocyte differentiation. The objectives of this study were to determine the effects of two- and threedimensional (2D and 3D) cultures of WJ-MSCs on hepatocyte differentiation. MSCs were isolated from human Wharton’s jelly, characterized by flow cytometry, and differentiated toward osteogenic and adipogenic lineage. WJ-MSCs were cultured in 2D collagen films and 3D collagen scaffolds in the presence of hepatogenic media with or without pre-treatment with fibroblast growth factor-4 (FGF4) for 21 days. The expression of HNF4α was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). According to flow cytometry data, the cells isolated from Wharton’s jelly were shown to express MSC markers. HNF4α expression analysis revealed that pre-exposing the cells with FGF4 was more effective in hepatocyte differentiation. 3D cultures also improve the expression of HNF4α compared with 2D culture system. In conclusion, the combination of FGF4 and 3D culture improved hepatocyte differentiation. It seems 3D interaction of the cells improved the hepatogenesis.
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    • "However, the availability of these cells for in vitro testing is limited (Guguen-Guillouzo and Guillouzo, 2010; LeCluyse, 2001). In addition, the quality of primary human hepatocytes is often compromised as they are usually obtained from liver biopsies of patients suffering from a liver disease or from post-mortem donated livers that are unsuitable for transplantation (Fitzpatrick et al., 2009). At present, the most plausible alternatives for primary human hepatocytes are hepatic cell lines such as HepG2 and HepaRG (Guguen-Guillouzo and Guillouzo, 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Besides their role in the elucidation of pathogenic processes of medical and pharmacological nature, biomarkers can also be used to document specific toxicological events. Hepatic cells generated from human skin-derived precursors (hSKP-HPC) were previously shown to be a promising in vitro tool for the evaluation of drug-induced hepatotoxicity. In this study, their capacity to identify potential liver-specific biomarkers at the gene expression level was investigated with particular emphasis on acute liver failure (ALF). To this end, a set of potential ALF-specific biomarkers was established using clinically relevant liver samples obtained from patients suffering from hepatitis B-associated ALF. Subsequently, this data was compared to data obtained from primary human hepatocyte cultures and hSKP-HPC, both exposed to the ALF-inducing reference compound acetaminophen. It was found that both in vitro systems revealed a set of molecules that was previously identified in the ALF liver samples. Yet, only a limited number of molecules was common between both in vitro systems and the ALF liver samples. Each of the in vitro systems could be used independently to identify potential toxicity biomarkers related to ALF. It seems therefore more appropriate to combine primary human hepatocyte cultures with complementary in vitro models to efficiently screen out potential hepatotoxic compounds.
    Full-text · Article · Oct 2014 · Toxicology in Vitro
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    • "However, due to the lack of transplantable donors, many patients died on the liver waiting list. Alternatively, hepatocyte transplantation has been proposed to partially recover liver function, and to extend the lifespan of patients until an organ becomes available [1], [2]. Therefore, the availability of an unlimited number of functional hepatocytes could greatly benefit patients with end-stage liver disease. "
    [Show abstract] [Hide abstract] ABSTRACT: Hepatocyte transplantation is considered to be a promising therapy for patients with liver diseases. Induced pluripotent stem cells (iPSCs) provide an unlimited source for the generation of functional hepatocytes. In this study, we generated iPSCs from porcine ear fibroblasts (PEFs) by overexpressing Sox2, Klf4, Oct4, and c-Myc (SKOM), and developed a novel strategy for the efficient differentiation of hepatocyte-like cells from porcine iPSCs by following the processes of early liver development. The differentiated cells displayed the phenotypes of hepatocytes, exhibited classic hepatocyte-associated bio-functions, such as LDL uptake, glycogen storage and urea secretion, as well as possessed the metabolic activities of cytochrome P-450 (CYP) 3A and 2C. Furthermore, we compared the hepatocyte differentiation efficacy of our protocol with another published method, and the results demonstrated that our differentiation strategy could significantly improve the generation of morphological and functional hepatocyte-like cells from porcine iPSCs. In conclusion, this study establishes an efficient method for in vitro generation of functional hepatocytes from porcine iPSCs, which could represent a promising cell source for preclinical testing of cell-based therapeutics for liver failure and for pharmacological applications.
    Full-text · Article · Jun 2014 · PLoS ONE
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