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New Approaches in the Differentiation of Human Embryonic Stem Cells and Induced Pluripotent Stem Cells toward Hepatocytes

Transplant Research Program, Department of Internal Medicine, University of California Davis Medical Center, 4635 2nd Ave. Suite 1001, Sacramento, CA 95817, USA.
Stem cell reviews (Impact Factor: 5.08). 02/2011; 7(3):748-59. DOI: 10.1007/s12015-010-9216-4
Source: PubMed

ABSTRACT Orthotropic liver transplantation is the only established treatment for end-stage liver diseases. Utilization of hepatocyte transplantation and bio-artificial liver devices as alternative therapeutic approaches requires an unlimited source of hepatocytes. Stem cells, especially embryonic stem cells, possessing the ability to produce functional hepatocytes for clinical applications and drug development, may provide the answer to this problem. New discoveries in the mechanisms of liver development and the emergence of induced pluripotent stem cells in 2006 have provided novel insights into hepatocyte differentiation and the use of stem cells for therapeutic applications. This review is aimed towards providing scientists and physicians with the latest advancements in this rapidly progressing field.

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    ABSTRACT: Background Human induced pluripotent stem cells, which can be differentiated into hepatocyte-like cells, could provide a source for liver regeneration and bio-artificial liver devices. However, the functionality of hepatocyte-like cells is significantly lower than that of primary hepatocytes. Aims To investigate whether serum from patients undergoing hepatectomy might promote differentiation from human induced pluripotent stem cells to hepatocyte-like cells. Methods Serum from patients undergoing hepatectomy (acquired pre-hepatectomy and 3 hours, 1 day and 3 days post-hepatectomy) was used to replace foetal bovine serum when differentiating human induced pluripotent stem cells into hepatocyte-like cells. Properties of hepatocyte-like cells were assessed and compared with cells cultured in foetal bovine serum. Results The differentiation efficiency and functionality of hepatocyte-like cells cultured in human serum 3 hours and 1 day post-hepatectomy were superior to those cultured in foetal bovine serum and human serum pre-hepatectomy. Human serum 3 days post-hepatectomy had an equal effect to that of human serum pre-hepatectomy. Some cytochrome P450 isozyme transcript levels of hepatocyte-like cells cultured in human serum were higher than those cultured in foetal bovine serum. Conclusion Human serum, particularly that acquired relatively soon after hepatectomy, can enhance the differentiation efficiency and functionality of hepatocyte-like cells derived from human induced pluripotent stem cells.
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    ABSTRACT: The scarcity of organs for liver transplant is a major pressure point of liver transplantation. Hence, generating hepatocytes may provide an alternative choice for therapeutic applications. At present, dental pulp stem cell (SCDs) is an emerging source in regenerative medicine. However, existing protocols for cell culture requires fetal bovine serum (FBS) as a nutritional supplement and may carry the risk of transmitting diseases. Therefore, the present study was undertaken to examine the efficacy of human platelet lysate (HPL) as a substitute for FBS in terms of proliferation and differentiation of SCDs into hepatic lineage cells. The result showed that HPL had displayed a superior effect on the proliferation of SCDs. Next, we induced SCDs into hepatic lineage cells which thrived by initiation and followed by maturation into functional hepatocytes for a total of 21 days. We observed that the gene, protein and its functional profile during this differentiation process reiterated in vivo liver development demonstrating a steady down-regulation of early endoderm markers (GATA4, GATA6, SOX17, HNF4α, HNF3β and AFP) with the up-regulation of hepatic specific markers (TDO, TO, TAT, ALB, AAT, CK18). We also noticed the presence of CK19 suggesting a progenitor population. To ascertain this, we checked for the expression of pluripotent markers and observed that it remained unchanged throughout the experiment period. Our results provide new insights on the ability of SCDs to differentiate into hepatic lineage cells and most remarkably, this can be done in autologous settings whereby both cell source and HPL can be derived from the same donor thus reducing the risk of disease transmission.
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