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Anil Dhawan - One of the best experts on this subject based on the ideXlab platform.

  • Hepatocyte Transplantation.
    Journal of clinical and experimental hepatology, 2020
    Co-Authors: Ragai R Mitry, Robin D Hughes, Anil Dhawan
    Abstract:

    Hepatocyte Transplantation (HTx) has been developed for use in liver-based metabolic disorders and in acute liver failure. Worldwide, there are around 80 patients that have been transplanted with Hepatocytes. Almost all reported studies prove feasibility and safety of the procedure with short- to medium-term success. Availability of good quality Hepatocytes (HCs) is the main limiting factor, and therefore alternative sources of cells such as stem cells are being investigated. Other limiting factors include cell engraftment, survival, and function of transplanted cells. It remains to be seen if progress in HTx research can overcome these hurdles leading to the wider use of the technique as an alternative to liver Transplantation in the future.

  • Hepatocyte Transplantation and advancements in alternative cell sources for liver-based regenerative medicine
    Journal of Molecular Medicine, 2018
    Co-Authors: Charlotte A Lee, Emer Fitzpatrick, Siddharth Sinha, Anil Dhawan
    Abstract:

    Human Hepatocyte Transplantation has been actively perused as an alternative to liver replacement for acute liver failure and liver-based metabolic defects. Current challenges in this field include a limited cell source, reduced cell viability following cryopreservation and poor engraftment of cells into the recipient liver with consequent limited life span. As a result, alternative stem cell sources such as pluripotent stem cells, fibroblasts, hepatic progenitor cells, amniotic epithelial cells and mesenchymal stem/stromal cells (MSCs) can be used to generate induced Hepatocyte like cells (HLC) with each technique exhibiting advantages and disadvantages. HLCs may have comparable function to primary human Hepatocytes and could offer patient-specific treatment. However, long-term functionality of transplanted HLCs and the potential oncogenic risks of using stem cells have yet to be established. The immunomodulatory effects of MSCs are promising, and multiple clinical trials are investigating their effect in cirrhosis and acute liver failure. Here, we review the current status of Hepatocyte Transplantation, alternative cell sources to primary human Hepatocytes and their potential in liver regeneration. We also describe recent clinical trials using Hepatocytes derived from stem cells and their role in improving the phenotype of several liver diseases.

  • human Hepatocyte Transplantation for liver disease current status and future perspectives
    Pediatric Research, 2018
    Co-Authors: Valeria Iansante, Ragai R Mitry, Celine Filippi, Emer Fitzpatrick, Anil Dhawan
    Abstract:

    Liver Transplantation is the accepted treatment for patients with acute liver failure and liver-based metabolic disorders. However, donor organ shortage and lifelong need for immunosuppression are the main limitations to liver Transplantation. In addition, loss of the native liver as a target organ for future gene therapy for metabolic disorders limits the futuristic treatment options, resulting in the need for alternative therapeutic strategies. A potential alternative to liver Transplantation is allogeneic Hepatocyte Transplantation. Over the last two decades, Hepatocyte Transplantation has made the transition from bench to bedside. Standardized techniques have been established for isolation, culture, and cryopreservation of human Hepatocytes. Clinical Hepatocyte Transplantation safety and short-term efficacy have been proven; however, some major hurdles—mainly concerning shortage of donor organs, low cell engraftment, and lack of a long-lasting effect—need to be overcome to widen its clinical applications. Current research is aimed at addressing these problems, with the ultimate goal of increasing Hepatocyte Transplantation efficacy in clinical applications.

  • instant blood mediated inflammatory reaction in Hepatocyte Transplantation current status and future perspectives
    Cell Transplantation, 2016
    Co-Authors: Anil Dhawan, Ragai R Mitry, Richard A G Smith, Emer Fitzpatrick
    Abstract:

    Hepatocyte Transplantation (HT) is emerging as a promising alternative to orthotopic liver Transplantation (OLT) in patients with certain liver-based metabolic disease and acute liver failure. Hepa...

  • current status of Hepatocyte Transplantation
    Transplantation, 2012
    Co-Authors: R D Hughes, Ragai R Mitry, Anil Dhawan
    Abstract:

    Hepatocyte Transplantation (HT) has been performed in patients with liver-based metabolic disease and acute liver failure as a potential alternative to liver Transplantation. The results are encouraging in genetic liver conditions where HT can replace the missing enzyme or protein. However, there ar

Ragai R Mitry - One of the best experts on this subject based on the ideXlab platform.

Stephen C Strom - One of the best experts on this subject based on the ideXlab platform.

  • Isolated Hepatocyte Transplantation in an infant with a severe urea cycle disorder.
    Pediatrics, 2020
    Co-Authors: Simon P Horslen, Timothy C Mccowan, Timothy C Goertzen, Phyllis I Warkentin, Stephen C Strom
    Abstract:

    Transplantation of isolated Hepatocytes in animal models has been shown to correct inborn errors of metabolism. Based on these studies and our experience with Hepatocyte Transplantation in a child with Crigler-Najjar syndrome, isolated Hepatocyte Transplantation was performed to attempt metabolic reconstitution in a male infant with severe ornithine transcarbamylase (OTC) deficiency. An infant with an antenatal diagnosis of OTC deficiency was managed intensively to prevent hyperammonemia. Isolated Hepatocytes were obtained by collagenase perfusion of donated livers not used for Transplantation. Hepatocytes were infused in batches over the first 4 weeks of life via an umbilical venous catheter positioned in the portal vein. Immunosuppression consisted of tacrolimus and corticosteroids. Over 4 billion viable Hepatocytes were transplanted during the first 3.5 weeks of life. A period of metabolic stability was achieved between days 20 and 31 during which normal protein intake was tolerated while phenylbutyrate was weaned. During this time, plasma ammonia and glutamine remained within normal limits. Hyperammonemia reappeared abruptly on day 31 of life. Protein tolerance diminished to baseline; metabolic stability was subsequently reattained only following successful liver Transplantation at 6 months of age. Isolated Hepatocyte Transplantation appeared to result in temporary relief of hyperammonemia and protein intolerance attributable to OTC deficiency. The metabolic stability achieved was lost after 11 days presumably because of rejection of the transplanted cells because of insufficient immunosuppression. Future attempts at isolated Hepatocyte Transplantation for inborn errors of metabolism in humans should include adequate immunosuppression and a liver biopsy as a means of proving Hepatocyte engraftment and function.

  • clinical Hepatocyte Transplantation what is next
    Current Transplantation Reports, 2017
    Co-Authors: James E Squires, Stephen C Strom, Kyle Soltys, Patrick Mckiernan, Robert H Squires, Alejandro Sotogutierrez
    Abstract:

    Purpose of Review Significant recent scientific developments have occurred in the field of liver repopulation and regeneration. While techniques to facilitate liver repopulation with donor Hepatocytes and different cell sources have been studied extensively in the laboratory, in recent years, clinical Hepatocyte Transplantation (HT) and liver repopulation trials have demonstrated new disease indications and also immunological challenges that will require the incorporation of a fresh look and new experimental approaches.

  • Hepatocyte Transplantation in Special Populations: Clinical Use in Children
    Methods of Molecular Biology, 2016
    Co-Authors: Zahida Khan, Stephen C Strom
    Abstract:

    Orthotopic liver Transplantation remains the only proven cure for end-stage liver failure. Despite significant advances in the field, the clinical demand for donor organs far outweighs the supply. Hepatocyte Transplantation has been proposed as an alternative approach to whole liver transplant in select diseases. Several international centers have reported experimental trials of human Hepatocyte Transplantation in acute liver failure and liver-based metabolic disorders. This chapter provides an introduction to Hepatocyte Transplantation from both a technical and clinical perspective. We will also focus on the special needs of pediatric patients, since historically the majority of clinical Hepatocyte transplants have involved infants and children.

  • Hepatocyte Transplantation for inherited metabolic diseases of the liver
    Journal of Internal Medicine, 2012
    Co-Authors: Carl Jorns, Stephen C Strom, Ewa Ellis, Greg Nowak, Bjorn Fischler, Antal Nemeth, Bogoran Ericzon
    Abstract:

    Inherited metabolic diseases of the liver are characterized by deficiency of a hepatic enzyme or protein often resulting in life-threatening disease. The remaining liver function is usually normal. For most patients, treatment consists of supportive therapy, and the only curative option is liver Transplantation. Hepatocyte Transplantation is a promising therapy for patients with inherited metabolic liver diseases, which offers a less invasive and fully reversible approach. Procedure-related complications are rare. Here, we review the experience of Hepatocyte Transplantation for metabolic liver diseases and discuss the major obstacles that need to be overcome to establish Hepatocyte Transplantation as a reliable treatment option in the clinic.

  • human Hepatocyte Transplantation
    Methods of Molecular Biology, 2010
    Co-Authors: Anil Dhawan, Stephen C Strom, Etienne Sokal
    Abstract:

    Over the last decade the interest in Hepatocyte Transplantation has been growing continuously and this treatment may represent an alternative clinical approach for patients with acute liver failure and life-threatening liver-based metabolic disorders. The technology also serves as the proof of concept and reference for future development in stem cell technology. This chapter reviews the field of Hepatocyte Transplantation from bench to bedside.

R D Hughes - One of the best experts on this subject based on the ideXlab platform.

  • current status of Hepatocyte Transplantation
    Transplantation, 2012
    Co-Authors: R D Hughes, Ragai R Mitry, Anil Dhawan
    Abstract:

    Hepatocyte Transplantation (HT) has been performed in patients with liver-based metabolic disease and acute liver failure as a potential alternative to liver Transplantation. The results are encouraging in genetic liver conditions where HT can replace the missing enzyme or protein. However, there ar

  • human Hepatocyte Transplantation current experience and future challenges
    Nature Reviews Gastroenterology & Hepatology, 2010
    Co-Authors: Anil Dhawan, Juliana Puppi, R D Hughes, Ragai R Mitry
    Abstract:

    Hepatocyte Transplantation has shown potential as an additional treatment modality for certain diseases of the liver, particularly liver-based metabolic disorders. The authors of this Review outline the current bench-to-beside experience with Hepatocyte Transplantation, and discuss the limitations that need to be overcome for its wider application.

  • liver after Hepatocyte Transplantation for liver based metabolic disorders in children
    Cell Transplantation, 2008
    Co-Authors: Alberto Quaglia, Ragai R Mitry, R D Hughes, Sharon C Lehec, Nigel Heaton, A S Knisely, Stephen Devereaux, Julie Richards, Mohamed Rela, Bernard Portmann
    Abstract:

    There are limited data regarding donor Hepatocyte engraftment into recipient liver after human Hepatocyte Transplantation (HHTx). We reviewed the explant livers of seven children with metabolic disorders [ornithine-transcarbamylase deficiency (one), coagulation factor VII deficiency (three), Crigler-Najjar syndrome (one), progressive familial intrahepatic cholestasis type 2 (PFIC-2) deficiency (two)] who received allograft Hepatocytes by intraportal infusion with improvement in phenotype, although all later underwent liver Transplantation (LT). Immunohistochemistry for bile salt export protein (BSEP) in the PFIC-2 patients and genetic typing following laser capture microdissection (LCM) of liver cells in the others were used to identify donor Hepatocytes in recipient explant livers. Explant livers usually showed a preserved lobular architecture. In one patient, Hepatocytes were identified inside portal vein thrombi. No donor Hepatocytes in liver cell plates were identified immunohistochemically or by gene...

  • Hepatocyte Transplantation followed by auxiliary liver Transplantation a novel treatment for ornithine transcarbamylase deficiency
    American Journal of Transplantation, 2008
    Co-Authors: Juliana Puppi, Ragai R Mitry, R D Hughes, Sharon C Lehec, Nigel Heaton, Giorgina Mielivergani, J Karani, M P Champion, R Mohamed, Anil Dhawan
    Abstract:

    We report the first successful use of Hepatocyte Transplantation as a bridge to subsequent auxiliary partial orthotopic liver Transplantation (APOLT) in a child antenatally diagnosed with severe ornithine transcarbamylase (OTC) deficiency. A total of 1.74 × 109 fresh and cryopreserved Hepatocytes were administered intraportally into the liver over a period of 6 months. Immunosuppression was with tacrolimus and prednisolone. A sustained decrease in ammonia levels and a gradual increase in serum urea were observed except during episodes of sepsis in the first 6 months of life. The patient was able to tolerate a normal protein intake and presented a normal growth and neurological development. APOLT was successfully performed at 7 months of age. We conclude that Hepatocyte Transplantation can be used in conjunction with APOLT as an effective treatment for severe OTC-deficient patients, improving neurodevelopmental outcomes.

  • Hepatocyte Transplantation for liver based metabolic disorders
    Journal of Inherited Metabolic Disease, 2006
    Co-Authors: Anil Dhawan, Ragai R Mitry, R D Hughes
    Abstract:

    Hepatocyte Transplantation is being investigated as an alternative to orthotopic liver Transplantation in patients with liver-based metabolic disorders. The progress made in this field to date is reviewed. Protocols have been developed using collagenase perfusion to isolate human Hepatocytes from unused donor liver tissue. Hepatocytes with a high viability can often be obtained and can be cryopreserved for later use, though with loss of function on thawing. For clinical use, Hepatocytes must be prepared in clean GMP conditions with cells meeting criteria of function and lack of microbial contamination before patient use. Hepatocytes are infused intraportally into the patient's liver, where a proportion of cells will engraft and replace the deficient metabolic function without the need for major surgery. Twenty patients have now received Hepatocyte Transplantation, including eight children at King's College Hospital. There was a range of aetiologies of liver disease: familial hypercholesterolaemia, Crigler-Najjar syndrome type 1, urea cycle defects, infantile Refsum disease, glycogen storage disease type Ia, inherited factor VII deficiency and progressive familial intrahepatic cholestasis type 2. Clinical improvement and partial correction of the metabolic abnormality was observed in most cases. Considerable progress has been made in developing the technique, but Hepatocyte Transplantation is limited by the available supply of liver tissue. Hepatocytes derived from stem cells could provide alternative sources of cells in the future.

Sanjeev Gupta - One of the best experts on this subject based on the ideXlab platform.

  • Hepatocyte Transplantation.
    Journal of gastroenterology and hepatology, 2020
    Co-Authors: Sanjeev Gupta
    Abstract:

    Repopulation of the liver with transplanted cells holds significant promise for developing novel therapies. The liver is a most suitable target for treating a variety of genetic, metabolic and acquired diseases. Liver disease, such as chronic viral hepatitis, constitutes an enormous burden worldwide. Advancing liver cell therapy requires insights into mechanisms of cell engraftment and proliferation, as well as unique requirements of specific diseases for correction by cell Transplantation. This review highlights recent developments in the area of Hepatocyte Transplantation. Aspects concerning modulation of cell engraftment, regulation of gene expression and proliferation of transplanted cells are discussed. Other issues concern the current status of clinical applications of Hepatocyte Transplantation, as well as novel sources of cells that could benefit cell therapy in the future. The general conclusion is that cell therapy has become more practical in recent years and insights into how the normal liver and the diseased liver can be repopulated will offer effective ways to treat many disorders in the near future.

  • Hepatocyte Transplantation induced liver inflammation is driven by cytokines chemokines associated with neutrophils and kupffer cells
    Gastroenterology, 2009
    Co-Authors: Natan Krohn, Sorabh Kapoor, Yuta Enami, Antonia Follenzi, Sriram Bandi, Brigid Joseph, Sanjeev Gupta
    Abstract:

    Background & Aims Hepatocyte Transplantation-induced liver inflammation impairs cell engraftment. We defined whether proinflammatory cytokines and chemokines played roles in regulation of Hepatocyte engraftment in the liver. Methods We performed studies over up to 3 weeks in rat Hepatocyte Transplantation systems. Expression of 84 cytokine-chemokine genes was studied by quantitative real-time polymerase chain reactions. Expression of selected up-regulated genes was verified by immunohistochemistry. Hepatic recruitment of neutrophils was demonstrated by myeloperoxidase activity assays, and Kupffer cell activation was established by carbon phagocytosis assays. The role of neutrophils and Kupffer cells in regulating expression of cytokine-chemokine genes as well as cell engraftment was determined by cell depletion studies. Results Within 6 hours after syngeneic cell Transplantation, expression of 25 cytokine-chemokine genes increased by 2- to 123-fold, P Conclusions Cell Transplantation-induced liver inflammation involves proinflammatory cytokine-chemokine systems capable of modulation by neutrophils and Kupffer cells. This offers new directions for optimizing cell therapy strategies.

  • Hepatocyte Transplantation new horizons and challenges
    Journal of Hepato-biliary-pancreatic Surgery, 2001
    Co-Authors: Harmeet Malhi, Sanjeev Gupta
    Abstract:

    Hepatocyte Transplantation represents an alternative strategy for treating liver disease. Liver repopulation following acute liver failure could, potentially, eliminate the requirement for orthotopic liver Transplantation. Similarly, the ability to repopulate the liver with disease-resistant Hepatocytes offers new opportunities for correcting genetic disorders and treating patients with chronic liver disease. Recent advances concerning the fate of transplanted cells in the recipient liver, the efficacy of cell therapy in outstanding animal models of human disease, and the isolation of progenitor liver cells capable of differentiating into mature Hepatocytes have renewed optimism in regard to treating people with Hepatocyte Transplantation. Recruitment of an increasing number of investigators to the field and the success of recent pilot studies indicate that Hepatocyte Transplantation will become routine clinical practice in the near future.

  • amelioration of radiation induced liver damage in partially hepatectomized rats by Hepatocyte Transplantation
    Cancer Research, 1999
    Co-Authors: Chandan Guha, Sanjeev Gupta, Anand Sharma, Alan A Alfieri, Giridhar R Gorla, S Gagandeep, Rana Sokhi, Namita Roychowdhury, Kathryn E Tanaka, B Vikram
    Abstract:

    Hepatic tumors often recur in the liver after surgical resection. Postoperative radiotherapy (RT) could improve survival, but curative RT may induce delayed life-threatening radiation-induced liver damage. Because RT inhibits liver regeneration, we hypothesized that unirradiated, transplanted Hepatocytes would proliferate preferentially in a partially resected and irradiated liver, providing metabolic support. We subjected F344 rats to hepatic RT and partial hepatectomy with/without a single intrasplenic, syngeneic Hepatocyte Transplantation. Hepatocyte Transplantation ameliorated radiation-induced liver damage and improved survival of rats receiving RT after partial hepatectomy. We further demonstrated that transplanted Hepatocytes extensively repopulate and function in a heavily irradiated rat liver.

  • Hepatocyte Transplantation: novel applications
    Liver Growth and Repair, 1998
    Co-Authors: Sanjeev Gupta
    Abstract:

    Hepatocyte Transplantation offers unexpected ways to analyze mechanisms of liver growth and repair. Survival of transplanted Hepatocytes is particularly relevant for therapeutic purposes, such as ex vivo gene therapy or novel cell-based therapies for acute liver failure. In designing experiments to define fundamental biological mechanisms or investigating the therapeutic potential of Hepatocytes, a number of considerations are important. Which site or sites might best support cell engraftment or survival? How might transplanted cells be localized in organs for unequivocal analysis of their fate? What strategies could be devised to analyze cell function or prolifera-tive capacity? Could pathophysiological insights into the organization of the liver lobule be surmised from analysis of isolated cell populations? Are satisfactory models available to define in controlled settings whether transplanted Hepatocytes could replace deficient metabolic function or aid recovery from liver failure? Overall, recent progress has been particularly exciting in three major areas — potential sites have been defined where transplanted Hepatocytes may engraft and survive, novel animal models have been developed to study mechanisms of liver re-population, and the therapeutic potential of Hepatocyte Transplantation has begun to be explored. The goal of this chapter is to describe the current status of Hepatocyte Transplantation in its various facets.