Toward the survival and function of xenogeneic hepatocyte grafts

Nishitai, Ryuta; Koch, Cody A.; Ogata, Kyoichi; Knudsen, Bruce E.; Plummer, Timothy B.; Butters, Kim A.; Platt, Jeffrey L.

doi:10.1002/lt.20305

Cited by 18 publications

(16 citation statements)

References 65 publications

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“…The livers were sequentially perfused with 5.0 liters of perfusate I (140 mM NaCl, 6.7 mM KCl, 10 mM acid-free HEPES, 2.5 mM EGTA, pH 7.4) followed by 2.0 liters of perfusate II (67 mM NaCl, 6.7 mM KCl, 100 mM HEPES, 4.8 mM CaCl 2 2H 2 O, 2 g collagenase D (Sigma-Aldrich), and 1% bovine serum albumin, pH 7.4), which was recirculated for 20 min as previously described (18). The viability of isolated hepatocytes was consistently Ͼ90% as assessed by exclusion of trypan blue.…”

Section: Cell Isolation and Culturementioning

confidence: 99%

Intrinsic Resistance of Hepatocytes to Complement-Mediated Injury

Koch

Kanazawa

Nishitai

et al. 2005

The Journal of Immunology

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When activated on or in the vicinity of cells, complement usually causes loss of function and sometimes cell death. Yet the liver, which produces large amounts of complement proteins, clears activators of complement and activated complexes from portal blood without obvious injury or impaired function. We asked whether and to what extent hepatocytes resist injury and loss of function mediated by exposure to complement. Using cells isolated from porcine livers as a model system, we found that, in contrast to endothelial cells, hepatocytes profoundly resist complement-mediated lysis and exhibit normal synthetic and conjugative functions when complement is activated on their surface. The resistance of hepatocytes to complement-mediated injury was not a function of cell surface control of the complement cascade but rather an intrinsic resistance of the cells dependent on the PI3K/Akt pathway. The resistance of hepatocytes to complement might be exploited in developing approaches to the treatment of hepatic failure or more broadly to the treatment of complement-mediated disease.

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Section: Cell Isolation and Culturementioning

confidence: 99%

Intrinsic Resistance of Hepatocytes to Complement-Mediated Injury

Koch

Kanazawa

Nishitai

et al. 2005

The Journal of Immunology

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“…The quality of isolated cells to be used for transplantation has been usually assessed based on cellular viability, plating efficiency, or plasma protein mRNA expression after a short period of culture (Baccarani et al, 2003;Mitry et al, 2003;Lloyd et al, 2004). Some discrepancies have been found in predictions of hepatocyte functionality after transplantation based on viability of isolated cells and survival in primary culture (Olinga et al, 2000;Nishitai et al, 2005). The functional competence of hepatocytes should also be used as an indication of the quality of cell preparations (Serralta et al, 2003).…”

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confidence: 99%

Potential Impact of Steatosis on Cytochrome P450 Enzymes of Human Hepatocytes Isolated from Fatty Liver Grafts

Donato

Lahoz²,

Jiménez³

et al. 2006

Drug Metabolism and Disposition

127

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ABSTRACT:Liver grafts discarded for transplantation because of macrosteatosis can constitute a valuable source of human hepatocytes for in vitro metabolic and pharmacotoxicological studies or for therapeutic applications. A condition for using hepatocyte suspensions for these purposes is the preservation of their metabolic competence and, particularly, drug-metabolizing enzymes. A reduction in microsomal cytochrome P450 (P450) activities was observed in fatty livers (>40% steatosis) with respect to normal tissue. Similarly, decreased levels of 7-ethoxycoumarin O-deethylation and testosterone metabolism were observed in human hepatocyte cultures prepared from steatotic liver tissue. To clarify the potential impact of lipid accumulation on human hepatic P450 enzymes, we have used an in vitro model of "cellular steatosis" by incubation of cultured hepatocytes with increasing concentrations (0.25-3 mM) of long-chain free fatty acids (FFA). A dose-dependent accumulation of lipids in the cytosol is induced by FFA mixture. Hepatocytes exposed to 1 mM FFA for 14 h showed lower activity values of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 enzymes than nontreated hepatocytes (about 45-65% reduction). This treatment also produced significant decreases in CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 mRNA to about 55 to 75% of mRNA levels in control cells. Our results suggest that although human hepatocytes isolated from steatotic liver show reduced P450 activities, they are metabolically competent and can be used for drug metabolism studies.

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“…Previous reports showed that cells intrasplenic cellular transplantation can cause impairment of hepatic microcirculation and hepatic function, and cause complications in the early transplantation [101,102]. Hence, certain methods have been developed to prevent the intrasplenic transplanted cells from migrating to the systemic circulation, such as the temporary complete occlusion of splenic vessel during infusion may reduce embolization, sudden death and portal hypertension [103][104][105].…”

Section: Intrasplenic Injectionmentioning

confidence: 99%

Therapeutic Potential of Adult Bone Marrow Stem Cells in Liver Disease and Delivery Approaches

Liu

2008

Stem Cell Rev

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Hematopoietic stem cells (HSCs) and mesenchymal stem cell (MSCs) are two main subtypes of bone marrow stem cells. Extensive studies have been carried out to investigate the therapeutic potential of BMSCs in liver disease. A number of animal and human studies demonstrated that either HSCs or MSCs could be applied to therapeutic purposes in certain liver diseases. The diseased liver may recruit migratory stem cells, particularly from the bone marrow, to generate hepatocyte-like cells either by transdifferentiation or cell fusion. Transplantation of BMSCs has therapeutic effects of restoration of liver mass and function, alleviation of fibrosis and correction of inherited liver diseases. There are still controversial results over the potential effects of BMSCs on liver diseases, and some of the discrepancies are thought to be lied in the differences of experimental protocols, differences in individual research laboratory, and the uncertainties of the techniques employed. Several potential approaches for BMSCs delivery in liver diseases have been proposed in animal studies and human trials. BMSCs can be delivered via intraportal vein, systemic infusion, intraperitoneal, intrahepatic, intrasplenic. The optimal stem cells delivery should be easy to perform, less invasive and traumatic, minimum side effects, and with high cells survival rate. In this review, we focus on the up-to-date evidence of therapeutic effects of BMSCs on liver disease, the characteristics of various delivery approaches, and the considerations for future studies.

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Toward the survival and function of xenogeneic hepatocyte grafts

Cited by 18 publications

References 65 publications

Intrinsic Resistance of Hepatocytes to Complement-Mediated Injury

Intrinsic Resistance of Hepatocytes to Complement-Mediated Injury

Potential Impact of Steatosis on Cytochrome P450 Enzymes of Human Hepatocytes Isolated from Fatty Liver Grafts

Therapeutic Potential of Adult Bone Marrow Stem Cells in Liver Disease and Delivery Approaches

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