Human Fetal Hepatocyte Transplantation in Patients With Fulminant Hepatic Failure

Cm, Habibullah; Ih, Syed; Qamar, Ali; Taher-Uz, Z

doi:10.1097/00007890-199410270-00016

Cited by 282 publications

(166 citation statements)

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“…The ability to rescue subjects with ALF by transplanting cells into the peritoneal cavity without reseeding of the liver will be of immense clinical significance in view of the simplicity of the former procedure. A few people with ALF have already been treated by transplantation of hepatocytes in the peritoneal cavity, 41 although those studies did not incorporate extracellular matrix support, without which hepatocytes are rapidly destroyed. We found that after cell therapy, abnormalities in hepatic gene expression reversed and liver regeneration was then completed by proliferation in previously growth-arrested native hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Bandi

Joseph

Berishvili

et al. 2011

The American Journal of Pathology

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Superior insights into molecular mechanisms of liver failure, which are not fully understood, will help strategies for inducing liver regeneration. We examined hepatotoxic mechanisms in mice homozygous for the severe combined immune deficiency mutation in the protein kinase, DNA-activated, catalytic polypeptide. Mice were treated with rifampicin, phenytoin, and monocrotaline. The ensuing acute liver failure was characterized by serological, histological, and mRNA studies. Subsequently, we studied whether transplantation of hepatocytes could rescue animals with liver failure. We found extensive liver damage in these animals, with mortality over several days. The expression of multiple hepatic genes was rapidly altered, including those representing pathways in oxidative/metabolic stress, inflammation, DNA damage-repair, and ataxia telangiectasia mutant (Atm) signaling pathways. This led to liver cell growth arrest involving cyclin-dependent kinase inhibitor 1A. Transplantation of hepatocytes with microcarriers in the peritoneal cavity efficiently rescued animals with liver failure. Molecular abnormalities rapidly reversed, including in hepatic Atm and downstream signaling pathways; and residual hepatocytes overcame cyclin-dependent kinase inhibitor 1A-induced cell growth arrest. Reseeding of the liver with transplanted hepatocytes was not required for rescue because native hepatocytes overcame cell growth-arrest to regenerate the liver. This likely resulted from paracrine signaling from hepatocytes in the peritoneal cavity. We concluded that Atm signaling Drug-induced liver injury (DILI) often results in acute liver failure (ALF). 1 Acetaminophen (APAP) is the leading offender in causing ALF; however, despite extensive work, mechanisms of DILI by APAP are incompletely understood. [2][3][4][5] The identification of molecular pathways initiating or amplifying DILI will be highly significant for drug development and for preventing and/or treating ALF. After exposure to hepatotoxic drugs, perturbations in cell stress and toxicity pathways assume prominence. However, more information is required regarding intracellular signaling pathways that impart susceptibility to DILI. Similarly, more information is required regarding failure of liver regeneration in ALF. Nevertheless, establishing these mechanisms has been difficult in the available animal models of ALF. For instance, after exposure to toxic drugs or chemicals, some animals may exhibit rapid and irreversible mortality (eg, within 24 -30 hours after APAP), whereas other animals may recover spontaneously.

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Section: Discussionmentioning

confidence: 99%

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Bandi

Joseph

Berishvili

et al. 2011

The American Journal of Pathology

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“…The common feature in these diseases is loss or defective hepatocyte function and the only curative therapy is orthotopic liver transplant. However, since there is a severe shortage of suitable donor organs, transplantation of human fetal and adult hepatocytes is being evaluated [3][4][5][6]. However, hepatocyte transplantation is limited by the severe shortage of suitable liver resections for cell isolation, the large number of hepatocytes required for transplantation and difficulties associated with hepatocyte culture and cryopreservation [7].…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte-Like Cells Derived from Human Amniotic Epithelial Cells Can Be Encapsulated Without Loss of Viability or Function In Vitro

Vaghjiani

Vaithilingam

Saraswati

et al. 2014

Stem Cells and Development

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Placenta derived human amniotic epithelial cells (hAEC) are an attractive source of stem cells for the generation of hepatocyte-like cells (HLC) for therapeutic applications to treat liver diseases. During hAEC differentiation into HLC, they become increasingly immunogenic, which may result in immune cell-mediated rejection upon transplantation into allogeneic recipients. Placing cells within devices such as alginate microcapsules can prevent immune cell-mediated rejection. The aim of this study was to investigate the characteristics of HLC generated from hAEC and to examine the effects of encapsulation on HLC viability, gene expression, and function. hAEC were differentiated for 4 weeks and evaluated for hepatocyte-specific gene expression and function. Differentiated cells were encapsulated in barium alginate microcapsules and cultured for 7 days and the effect of encapsulation on cell viability, function, and hepatocyte related gene expression was determined. Differentiated cells performed key functions of hepatocytes including urea synthesis, drug-metabolizing cytochrome P450 (CYP)3A4 activity, indocyanine green (ICG) uptake, low-density lipoprotein (LDL) uptake, and exhibited glutathione antioxidant capacity. A number of hepatocyte-related genes involved in fat, cholesterol, bile acid synthesis, and xenobiotic metabolism were also expressed showing that the hAEC had differentiated into HLC. Upon encapsulation, the HLC remained viable for at least 7 days in culture, continued to express genes involved in fat, cholesterol, bile acid, and xenobiotic metabolism and had glutathione antioxidant capacity. CYP3A4 activity and urea synthesis by the encapsulated HLC were higher than that of monolayer HLC cultures. Functional HLC can be derived from hAEC, and HLC can be encapsulated within alginate microcapsules without losing viability or function in vitro.

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“…This is especially the case for hepatic progenitors isolated from human livers. Hepatic progenitors represent a population with potential advantages over total liver cell suspensions or hepatocytes for cell transplantation in patients (29,128), for review see (129). Because of their high proliferation and differentiation potential a major advantage for transplantation of stem cells over total liver cell suspensions would be the requirement for less cell numbers to inject, which would decrease the risks associated with transplanting high cell numbers.…”

Section: Resultsmentioning

confidence: 99%

Hepatic Progenitors of the Liver and Extra-Hepatic Tissues

Schmelzer¹

2012

Liver Regeneration

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Human Fetal Hepatocyte Transplantation in Patients With Fulminant Hepatic Failure

Cited by 282 publications

References 0 publications

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Hepatocyte-Like Cells Derived from Human Amniotic Epithelial Cells Can Be Encapsulated Without Loss of Viability or Function In Vitro

Hepatic Progenitors of the Liver and Extra-Hepatic Tissues

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