Clinical human hepatocyte transplantation: Current status and challenges

Dhawan, Anil

doi:10.1002/lt.24226

Cited by 46 publications

(42 citation statements)

References 60 publications

(110 reference statements)

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“…In fact, despite promising 1-year islet allograft survival rates in diabetic patients, the majority of recipients are not insulin free at 3 years posttransplant 15,16 . Similarly, allogeneic hepatocyte grafts transplanted into patients with metabolic disorders or liver failure exhibit significant but short-lived benefits ranging 3–26 months posttransplant 13,17–19 . This disparity, between whole liver transplantation and parenchymal cell transplants implanted into the liver, may be explained by a tightly regulated balance between immune reactivity and tolerance within the liver immune environment 10,20 .…”

Section: Introductionmentioning

confidence: 99%

Unique CD8+ T Cell–Mediated Immune Responses Primed in the Liver

et al. 2016

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Background The liver immune environment is tightly regulated to balance immune activation with immune tolerance. Understanding the dominant immune pathways initiated in the liver is important since the liver is a site for cell transplantation, such as for islet and hepatocyte transplantation. The purpose of this study is to examine the consequences of alloimmune stimulation when allogeneic cells are transplanted to the liver in comparison to a different immune locale, such as the kidney. Methods We investigated cellular and humoral immune responses when allogeneic hepatocytes are transplanted directly to the recipient liver by intraportal injection. A heterotopic kidney engraftment site was used for comparison to immune activation in the liver microenvironment. Results Transplantation of allogeneic hepatocytes delivered directly to the liver, via recipient portal circulation, stimulated long-term, high magnitude CD8+ T cell-mediated allocytotoxicity. CD8+ T cells initiated significant in vivo allocytotoxicity as well as rapid rejection of hepatocytes transplanted to the liver even in the absence of secondary lymph nodes or CD4+ T cells. In contrast, in the absence of recipient peripheral lymphoid tissue and CD4+ T cells, CD8-mediated in vivo allocytotoxicity was abrogated and rejection was delayed when hepatocellular allografts were transplanted to the kidney subcapsular site. Conclusions These results highlight the CD8-dominant proinflammatory immune responses unique to the liver microenvironment. Allogeneic cells transplanted directly to the liver do not enjoy immune privilege but rather require immunosuppression to prevent rejection by a robust and persistent CD8‐dependent allocytotoxicity primed in the liver.

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Section: Introductionmentioning

confidence: 99%

Unique CD8+ T Cell–Mediated Immune Responses Primed in the Liver

et al. 2016

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“…T h e o p t i m a l r e p r o g r a m m i n g m e t h o d w i t h n o impact on the cell genome is not yet established and reprogrammed cells lack sufficient maturity for widespread clinical use (2,5). In keeping, the small molecule-based reprogramming has attracted much interest due to its safety and efficiency in controlling cell fates (12); this methodology has been successfully used for fibroblast reprogramming into iPS or neurons (13).…”

Section: Editorialmentioning

confidence: 99%

“…Cell therapies with mature hepatocytes have provided encouraging results in several clinical trials and adult hepatocyte transplantation has been indicated as a promising alternative to OLT for the treatment of some liver-based metabolic disorders or acute liver failure (5); unfortunately, the effects of hepatocyte transplantation are transient and cell function appears to decline after few months; moreover, cell transplantation procedures cause complications and require immunosuppression (5). Actually, one of the main obstacles to the clinical application of hepatocyte transplantation resides in sourcing of cells and in difficulties in cryopreservation, and in low engraftment (5).…”

mentioning

confidence: 99%

“…Actually, one of the main obstacles to the clinical application of hepatocyte transplantation resides in sourcing of cells and in difficulties in cryopreservation, and in low engraftment (5). Isolation of primary human hepatocytes competes with organs for OLT; therefore, current sources of tissue for hepatocyte isolation are limited and of marginal quality, such as adult organs that are unsuitable for OLT, livers that have undergone aggressive therapies, or surrounding liver parenchyma obtained after tumor excision (5). As regard, cryopreserved cells, absence of proliferation and reduced functions of thawed hepatocytes damper their potential for cell therapies (5).…”

mentioning

confidence: 99%

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Cell sources for regenerative medicine of the liver and endoderm organs: strategies and perspectives

Carpino

Gaudio

2016

Stem Cell Investig.

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“…Two types of cell-based treatment modalities are under development: Bioartificial Liver (BAL) therapy [2][3][4] and hepatocyte transplantation [5,6].…”

Section: Introductionmentioning

confidence: 99%

HepaRG-Progenitor Cell Derived Hepatocytes Cultured in Bioartificial Livers Are Protected from Healthy- and Acute Liver Failure-Plasma Induced Toxicity

Wenum¹,

Treskes²,

Adam³

et al. 2018

Cell Physiol Biochem

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Background/Aims: For applicability of cell-based therapies aimed at the treatment of liver failure, such as bioartificial livers (BALs) and hepatocyte transplantation, it is essential that the applied hepatocytes tolerate exposure to the patient plasma. However, plasma from both healthy donors and acute liver failure (ALF) patients is detrimental to hepatocytes and hepatic cell lines, such as HepaRG. We aimed to elucidate the underlying mechanisms of plasma-induced toxicity against HepaRG cells in order to ultimately develop methods to reduce this toxicity and render HepaRG-BAL treatment more effective. Methods: Differentiated HepaRG cells cultured in monolayers and laboratory-scale BALs were exposed to culture medium, healthy human plasma, healthy porcine plasma and ALF porcine plasma. Healthy human plasma was fractionated based on size- and polarity, albumin depleted and heat treated to characterize the toxic fraction. The cells were assessed for viability by total protein content and trypan blue staining. Their hepatic differentiation was assessed on transcript level through qRT-PCR and microarray analysis, and on functional level for Cytochrome P450 3A4 activity and ammonia elimination. Mitochondrial damage was assessed by JC-1 staining and mitochondrial gene transcription. Results: Sixteen hours of healthy human plasma exposure did not affect viability, however, hepatic gene-transcript levels decreased dramatically and dose-dependently within four hours of exposure. These changes were associated with early NF-kB signaling and a shift from mitochondrial energy metabolism towards glycolysis. Healthy human plasma-toxicity was associated with the dose-dependent presence of heat-resistant, albumin-bound and (partly) hydrophobic toxic compound(s). HepaRG cells cultured in BALs were partially protected from plasma-toxicity, which was mainly attributable to medium perfusion and/or 3D configuration applied during BAL culturing. The detrimental human plasma effects were reversible in BAL-cultured cells. Porcine ALF-plasma elicited mitotoxicity additional to the basal detrimental effect of porcine healthy plasma, which were only partially reversible. Conclusion: A specific fraction of human plasma reduces hepatic differentiation of HepaRG cultures, in association with early NF-κB activation. In addition, ALF-plasma elicits mitotoxic effects. These findings allow for a targeted approach in preventing plasma-induced cell damage.

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Clinical human hepatocyte transplantation: Current status and challenges

Cited by 46 publications

References 60 publications

Unique CD8+ T Cell–Mediated Immune Responses Primed in the Liver

Unique CD8+ T Cell–Mediated Immune Responses Primed in the Liver

Cell sources for regenerative medicine of the liver and endoderm organs: strategies and perspectives

HepaRG-Progenitor Cell Derived Hepatocytes Cultured in Bioartificial Livers Are Protected from Healthy- and Acute Liver Failure-Plasma Induced Toxicity

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