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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    • "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). "
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    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.
    Toxicology in Vitro 10/2014; 29(6). DOI:10.1016/j.tiv.2014.10.012 · 2.90 Impact Factor
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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. "
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    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.
    PLoS ONE 06/2014; 9(6):e100417. DOI:10.1371/journal.pone.0100417 · 3.23 Impact Factor
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    • "Bone marrow stem cells (BMSCs) can repopulate an injured liver, differentiate into mature hepatocytes in vitro, and participate in liver regeneration 8, 16, 21. BMSC transplantation has been used to improve a mouse model of tyrosinemia 9, 22 and an inborn defect in a hepatocytic enzyme 1, 4, 5 by reconstituting the architecture and function of the injured liver. Our previous studies have demonstrated that acute hepatic failure-derived rat BMSCs have a hepatic transcriptional profile, expressing many of the same genes expressed by hepatocytes 23, 24. "
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    ABSTRACT: Objective: To clarify the precise characteristics of human hepatic progenitor cells (HPCs) for future cytotherapy in liver diseases. Methods: Hepatic progenitor-like cells were isolated and cultured from the livers of patients who had undergone partial hepatectomy for various pathologies but displayed no sign of hepatic dysfunction. These cells were characterized by transcriptomic profiling, quantitative real-time PCR and immunocyto/histochemistry. Results:Cultured HPCs contained polygonal, high nucleus/cytoplasm ratio and exhibited a global gene expression profile similar (67.8%) to that of primary hepatocytes. Among the genes with more than 20-fold higher expression in HPCs were a progenitor marker (CD90), a pentraxin-related gene (PTX3), collagen proteins (COL5A2, COL1A1 and COL4A2), cytokines (EGF and PDGFD), metabolic enzymes (CYBRD1, BCAT1, TIMP2 and PAM), a secreted protein (SPARC) and an endothelial protein C receptor (PROCR). Moreover, eight markers (ALB, AFP, CK8, CK18, CK19, CD90, CD117 and Oval-6) previously described as HPC markers were validated by qRT-PCR and/or immunocyto/histochemistry. Interestingly, human HPCs were also positive for the hematopoietic cell markers CD45 and CD109. Finally, we characterized the localization of HPCs in the canals of Hering and periportal areas with six previously described markers (Oval-6, CK8, CK18, CK19, CD90 and CD117) and two potential markers (CD45 and CD109). Conclusion: The human HPCs are highly similar to primary hepatocytes in their transcriptional profiles. The CD45 and CD109 markers could potentially be utilized to identify and isolate HPCs for further cytotherapy of liver diseases.
    International journal of medical sciences 12/2013; 11(1):65-79. DOI:10.7150/ijms.7426 · 2.00 Impact Factor
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