In utero transplanted human hepatocytes allow postnatal engraftment of human hepatocytes in pigs

Fisher, James E.; Lillegard, Joseph B.; McKenzie, Travis J.; Rodysill, Brian; Wettstein, Peter J.; Nyberg, Scott L.

doi:10.1002/lt.23598

Cited by 32 publications

(33 citation statements)

References 29 publications

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“…[50] As liver injury can be initiated by stopping NTBC at any time in development, FAH −/− pigs could be used to test efficacy of gene therapy and in utero cell transplant approaches at any point during gestation, providing a unique disease model that is currently unavailable. Additionally, FAH-deficiency during development may provide a strong selective advantage for the expansion of transplanted human hepatocytes in utero,[51] potentially allowing rapid repopulation of the FAH −/− liver with cells[42] that could be used for various cell therapy approaches for myriad liver disorders. A comparable strategy has already been demonstrated in the pig for generating exogenic pancreas in an apancreatic pig by way of blastocyst complementation.…”

Section: Section 4: Discussionmentioning

confidence: 99%

Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease

et al. 2014

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Hereditary tyrosinemia type I (HT1) is caused by deficiency in fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the last step of tyrosine metabolism. The most severe form of the disease presents acutely during infancy, and is characterized by severe liver involvement, most commonly resulting in death if untreated. Generation of FAH+/− pigs was previously accomplished by adeno-associated virus-mediated gene knockout in fibroblasts and somatic cell nuclear transfer. Subsequently, these animals were outbred and crossed to produce the first FAH−/− pigs. FAH-deficiency produced a lethal defect in utero that was corrected by administration of 2-(2-nitro-4-trifluoromethylbenzyol)-1,3 cyclohexanedione (NTBC) throughout pregnancy. Animals on NTBC were phenotypically normal at birth; however, animals were euthanized approximately four weeks after withdrawal of NTBC due to clinical decline and physical examination findings of severe liver injury and encephalopthy consistent with acute liver failure. Biochemical and histological analyses, characterized by diffuse and severe hepatocellular damage, confirmed the diagnosis of severe liver injury. FAH−/− pigs provide the first genetically engineered large animal model of a metabolic liver disorder. Future applications of FAH−/− pigs include discovery research as a large animal model of HT1 and spontaneous acute liver failure, and preclinical testing of efficacy of liver cell therapies, including transplantation of hepatocytes, liver stem cells, and pluripotent stem cell-derived hepatocytes.

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Section: Section 4: Discussionmentioning

confidence: 99%

Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease

et al. 2014

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“…12 Fisher et al injected human hepatocytes directly into the fetal pig liver on gestational day 40 and again 1 week after birth, resulting in successful engraftment of human hepatocyte in postnatal pigs. 13 Although this concept enables effective development of organs, it is inevitable that some xenogeneic components remain in the engineered organs. Furthermore, the maintenance of transplanted human cells in a pig scaffold is also important.…”

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confidence: 99%

“…The recent achievements in both rodent and pig models are summarized in Table 1. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] One of the approaches is to utilize the organogenetic potential of scaffold animals. Although it is still hard to control complex of signals and interactions for organ development, this concept allows cells to make use of almost optimal environment.…”

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confidence: 99%

Transplantable liver production plan

2013

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Organ grafts developed in the xenogeneic pig scaffold are expected to resolve most issues of donor safety and ethical concerns about living-donor liver transplantation in Japan. We have been working on so-called "Yamaton" projects to develop transplantable organs using genetically engineered pigs. Our goal is to produce chimeric livers with human parenchyma in such pigs. The Yamaton-Liver project demonstrated the proof of concept by showing that rat-mouse chimeric livers could develop in mice and be successfully transplanted into syngeneic or allogeneic rats. Under conventional immunosuppression, the transplanted livers showed long-term function and protection against rejection. Because chimeric liver grafts have xenogeneic components, additional strategies, such as humanization of pig genes, induction of hematopoietic chimeras in donors, and replacement of pig endothelial cells with human ones, might be required in clinical use. Our projects still need to overcome various hurdles but can bring huge benefits to patients in the future.

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“…A number of studies have shown hepatocyte engraftment and function across a species barrier, but while the exclusion of vascular structures may address some of the immunological issues associated with xenotransplantation, the possibility of xenozoonosis remains (14). Another viable option in the future may be the use of fumarylacetoacetate hydrolase (FAH) deficient pigs as incubators for in vivo expansion of human hepatocytes, as in utero cell transplantation can lead to postnatal engraftment of functional human cells in the xenogeneic recipient, possibly allowing for large-scale expansion of human hepatocytes in genetically-engineered pigs (15). Stem cells are also a potential source of hepatocyte-like cells (HLCs), and will be discussed in the following section.…”

Section: Primary Hepatocytesmentioning

confidence: 99%

Cell therapy in chronic liver disease

Nicolas

Wang

Nyberg

2016

Current Opinion in Gastroenterology

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Purpose of review To date, the only curative treatment for end-stage liver disease is liver transplantation, which is limited by the shortage of available organs. Cell therapy, in the form of cell transplantation or cell-based extracorporeal support devices, may in the future offer an alternative to transplantation, or at least provide liver function support as a bridging therapy until surgery may be performed. The purpose of this review is to highlight the most recent advances made in the field of cell therapy and regenerative medicine for the treatment of chronic liver disease (CLD). Recent findings After hepatocyte transplantation, long-term engraftment in the liver and spleen may be achieved, which can be stimulated through preconditioning, multiple infusions, and inflammatory response blockade. Mesenchymal stem cells are promising candidates for cell transplantation, as they have been shown to reduce liver fibrosis and support endogenous regeneration. Adipose tissue-derived stem cells are also being tested in this setting, due to their ready availability. Bioartificial liver (BAL) devices are being built that allow for effective preservation of hepatocytes, and one such device has recently demonstrated survival benefit in a porcine model of liver failure. Summary Cell transplantation of primary hepatocytes or stem cell-derived hepatocyte-like cells (HLCs) for the treatment of CLD holds promise. BAL systems may in the future be able to bridge acute-on-chronic liver failure patients to liver transplantation.

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In utero transplanted human hepatocytes allow postnatal engraftment of human hepatocytes in pigs

Cited by 32 publications

References 29 publications

Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease

Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease

Transplantable liver production plan

Cell therapy in chronic liver disease

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