Hepatocyte transplantation: Back to the future

Gupta, Sanjeev; Chowdhury, Jayanta Roy

doi:10.1002/hep.1840150126

Cited by 95 publications

(34 citation statements)

References 71 publications

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“…46,47 Particularly for the treatment of inherited metabolic disease, a technique for transplantation of genetically modified autologous hepatocytes, which have the advantage of no T cell-mediated rejection, is being developed. Although the host liver represents an ideal site for transplanted hepatocytes in terms of the unique hepatic organization and interactions with nonparenchymal liver cells, 48 insufficient intrahepatic engraftment of transplanted hepatocytes, even those that are autologous, remains a major obstacle. It has been demonstrated that transplanted hepatocytes become stacked at the portal vein radices, resulting in deposition of some of the cells at the hepatic sinusoid.…”

Section: Discussionmentioning

confidence: 99%

Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

et al. 2004

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Section: Discussionmentioning

confidence: 99%

Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

et al. 2004

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“…Examples include deficiency states with a hepatic basis that spare the liver from injury, such as familial hypercholesterolemia, 11 as well as acute liver failure. 1,2 Present evidence indicates that transplanted hepatocytes do not undergo significant proliferation in the normal liver. 12 One strategy to extensively repopulate the normal liver will be to repeatedly transplant large numbers of cells.…”

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confidence: 95%

Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium

et al. 1999

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To establish the process by which transplanted cells integrate into the liver parenchyma, we used dipeptidyl peptidase IV-deficient F344 rats as hosts. On intrasplenic injection, transplanted hepatocytes immediately entered liver sinusoids, along with attenuation of portal vein radicles on angiography. However, a large fraction of transplanted cells (Ͼ70%) was rapidly cleared from portal spaces by phagocyte/macrophage responses. On the other hand, transplanted hepatocytes entering the hepatic sinusoids showed superior survival. These cells translocated from sinusoids into liver plates between 16 and 20 hours after transplantation, during which electron microscopy showed disruption of the sinusoidal endothelium. Interestingly, production of vascular endothelial growth factor was observed in hepatocytes before endothelial disruptions. Portal hypertension and angiographic changes resulting from cell transplantation resolved promptly. Integration of transplanted hepatocytes in the liver parenchyma required cell membrane regenesis, with hybrid gap junctions and bile canaliculi forming over 3 to 7 days after cell transplantation. We propose that strategies to deposit cells into distal hepatic sinusoids, to disrupt sinusoidal endothelium for facilitating cell entry into liver plates, and to accelerate cell integrations into liver parenchyma will advance applications of hepatocyte transplantation. (HEPATOLOGY 1999;29:509-519.)

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“…Currently, much is known about the isolation of hepatocytes, their ability to be manipulated in vitro, the best route of administration for transplantation, and the regeneration process in vivo. 100 Although hepatocytes cultured as monolayers in vitro exhibit minimal mitotic activity and maintain several major metabolic functions characteristic of normal liver including albumin synthesis and secretion, glycogen synthesis, and microsomal enzyme activity, these hepatocytes fail to sustain high rates of transcription of most liver-specific messenger RNAs. 101,102 These primary hepatocytes do not serve as an optimal environment for HCV infection or replication, but the maintenance of hepatocyte function in vivo through transplanted hepatocytes may provide the necessary extracellular matrix components, growth factors and interaction with other liver cells not available in tissue culture to support efficient replication of HCV.…”

Section: Xenograft Modelsmentioning

confidence: 99%

Bad time for Bonzo? Experimental models of hepatitis C virus infection, replication, and pathogenesis

2001

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Hepatitis C virus (HCV)-induced chronic hepatitis with concomitant cirrhosis and hepatocellular carcinoma is now the leading cause of liver transplantation in the United States. 1 There are currently nearly 3 million HCV carriers in the U.S. (ϳ2% of the population) and an estimated 170 million people worldwide. In 20% of patients, HCV infection is naturally cleared after several months, 2-4 but the majority of patients are chronic carriers who, in addition to being the source for most new infections, can progress to chronic active hepatitis with cirrhosis and/or hepatocellular carcinoma. Despite the increasing prevalence of HCV infection and its potentially grave clinical consequences, the only licensed therapy for chronic hepatitis is interferon ␣, either alone or in combination with ribavirin. This therapy is expensive, not effective in all HCV patients, and laden with significant side effects. 5 Unfortunately, the development of innovative treatment alternatives for HCV-infected patients has been impeded by the lack of in vitro and in vivo systems suitable for the study of HCV infection, replication, and pathogenesis.Since the successful transmission of hepatitis C to chimpanzees in 1978 6,7 and the molecular cloning of HCV as its etiologic agent in 1989, 8 the hepatitis C virus has been extensively studied and characterized at the molecular level. The virus is an enveloped flavivirus whose genome is a 9.6-kb, single-stranded RNA with positive polarity consisting of a 5Ј nontranslated region (NTR), a large open reading frame encoding all virus-specific proteins, and a 3Ј NTR. The structural proteins (C, E1, and E2) are located at the N-terminus of the polyprotein, while the virus-specific RNA polymerase and other nonstructural proteins are encoded in the remainder. 4 The enzymology of the viral replication proteins has been studied in detail and it is known that HCV RNA replication is error prone leading to the continuous generation of viral variants. Indeed, different quasispecies have been isolated from the same patient at different points in time, and have indicated the presence of multiple viral sequences located in the hypervariable region of the E1 and E2 genes. 9-11 While this dynamic variation may be important for the establishment and maintenance of persistent infection, its actual significance has been difficult to study with current technology. HCV REPLICATION IN CELL CULTUREThe investigation of many critical questions in the field of HCV research would benefit greatly by successfully achieving full replication of HCV in an experimental system. Continuous hepatoma, B-cell and T-cell lines, primary hepatocytes from humans and chimpanzees, and peripheral blood mononuclear cells have all been reported to support HCV replication. 12 Unfortunately, none has been robust enough to permit classic virologic, biochemical or genetic dissection of the HCV replication cycle. Thus, the mechanism of viral attachment and cellular entry and the precise intracellular steps in HCV-RNA replication, virus assembly, and...

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Hepatocyte transplantation: Back to the future

Cited by 95 publications

References 71 publications

Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

Entry and integration of transplanted hepatocytes in rat liver plates occur by disruption of hepatic sinusoidal endothelium

Bad time for Bonzo? Experimental models of hepatitis C virus infection, replication, and pathogenesis

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