Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Wu, Yao‐Ming; Joseph, Brigid; Gupta, Sanjeev

doi:10.1002/hep.21277

Cited by 23 publications

(32 citation statements)

References 31 publications

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“…The present study does not include measurement of these detailed parameters, but our overall findings are similar to the study by Wu et al, 33 protocol) for both the SRL monotherapy and SRL + CsA groups. The influence of SRL can easily explain the differences in the survival rate and histological findings described in present study.…”

Section: Discussionsupporting

confidence: 88%

Xenotransplantation of Hepatocytes in Rats with Acute Liver Failure Using Sirolimus for Immunosuppression

et al. 2010

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Section: Discussionsupporting

confidence: 88%

Xenotransplantation of Hepatocytes in Rats with Acute Liver Failure Using Sirolimus for Immunosuppression

et al. 2010

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“…We consider that the central mechanism responsible for liver repopulation in MCT-treated mice involves loss of native cells, thereby requiring healthy transplanted cells to proliferate. Although cell transplantation in the liver transiently activates Kupffer cells, stellate cells and endothelial cells with hepatic expression of trophic, for example, hepatocyte growth factor, vascular endothelial growth factor, matrix-remodeling, metalloproteinases, and other genes that affect cell engraftment, 2,3,30,31 whether transplanted cell proliferation during liver repopulation is regulated by specific factors released by liver cells is unknown. Nonetheless, because transplanted cells retain physiologically regulated function after liver repopulation, 6,7 including in animal models of disease, 9,26,32 our findings should offer impetus for drug-based strategies to damage the native liver before cell transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4] It was noteworthy that transplanted cells did not proliferate in the normal liver, where cell turnover is minimal, although, depending on the extent of injury in native cells, proliferation in healthy transplanted cells was activated. 5,6 In this way, transplanted cells could repopulate the liver, where in specific situations the kinetics of liver repopulation reflected loss of native hepatocytes.…”

mentioning

confidence: 99%

“…[13][14][15][16] Previously, we developed suitable mechanisms in mutant rats lacking dipeptidyl peptidase IV enzyme activity (DPPIVϪ rats) to determine the fate of transplanted cells. 2,3,[5][6][7] To determine whether transplanted cells could be used as reporters to identify changes in liver cell compartments, we used DPPIVϪ mice as recipients of healthy cells. Our studies established that transplanted reporter cells effectively identified perturbations in the hepatic endothelial and parenchymal cell compartments.…”

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confidence: 99%

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Hepatocyte transplantation and drug-induced perturbations in liver cell compartments

Wu¹,

Joseph²,

Berishvili³

et al. 2007

Hepatology

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The potential for organ damage after using drugs or chemicals is a critical issue in medicine. To delineate mechanisms of drug-induced hepatic injury, we used transplanted cells as reporters in dipeptidyl peptidase IV-deficient mice. These mice were given phenytoin and rifampicin for 3 days, after which monocrotaline was given followed 1 day later by intrasplenic transplantation of healthy C57BL/6 mouse hepatocytes. We examined endothelial and hepatic damage by serologic or tissue studies and assessed changes in transplanted cell engraftment and liver repopulation by histochemical staining for dipeptidyl peptidase IV. Monocrotaline caused denudation of the hepatic sinusoidal endothelium and increased serum hyaluronic acid levels, along with superior transplanted cell engraftment. Together, phenytoin, rifampicin, and monocrotaline caused further endothelial damage, reflected by greater improvement in cell engraftment. Phenytoin, rifampicin, and monocrotaline produced injury in hepatocytes that was not apparent after conventional tissue studies. This led to transplanted cell proliferation and extensive liver repopulation over several weeks, which was more efficient in males compared with females, including greater induction by phenytoin and rifampicin of cytochrome P450 3A4 isoform that converts monocrotaline to toxic intermediates. Through this and other possible mechanisms, monocrotaline-induced injury in the endothelial compartment was retargeted to simultaneously involve hepatocytes over the long term. Moreover, after this hepatic injury, native liver cells were more susceptible to additional pro-oxidant injury through thyroid hormone, which accelerated the kinetics of liver repopulation. Conclusion: Transplanted reporter cells will be useful for obtaining insights into homeostatic mechanisms involving liver cell compartments, whereas targeted injury in hepatic endothelial and parenchymal cells with suitable drugs will also help advance liver cell therapy. ( T o obtain fresh paradigms in tissue homeostasis after exposure to drugs or chemicals, 1 we considered that reporter cells will help elucidate perturbations in the liver, because genetically marked reporter cells can be inserted into liver compartments, including the parenchyma or hepatic endothelium. 2-4 It was noteworthy that transplanted cells did not proliferate in the normal liver, where cell turnover is minimal, although, depending on the extent of injury in native cells, proliferation in healthy transplanted cells was activated. 5,6 In this way, transplanted cells could repopulate the liver, where in specific situations the kinetics of liver repopulation reflected loss of native hepatocytes. [7][8][9] In healthy animals, genotoxic manipulations were particularly effective in promoting such liver repopulation with healthy cells. However, further insights are necessary to obtain pharmacologic approaches for repopulating the liver, particularly for clinical applications.To develop cell compartment-specific hepatic perturbations, we used monocrotaline (...

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“…TNF-a, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and interferon-inducible protein-10 were analyzed by semiquantitative RT-PCR, as described previously (14). Real-time quantitative PCR (qPCR) was performed with commercially available primers for rat TNF-a and b-actin (MGC124630, reference sequence NM012675; and PRR06570B, reference sequence NM031144, respectively; SA Biosciences).…”

Section: Reverse-transcription Polymerase Chain Reaction (Rt-pcr)mentioning

confidence: 99%

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Bhargava¹,

Joseph²,

Ananthanarayanan³

et al. 2009

J Nucl Med

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The organic anion 99m Tc-N-[2- [(3-bromo-2,4,6-trimethylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)-glycine ( 99m Tc-mebrofenin) and its analogs are widely used for hepatobiliary imaging. Identification of the mechanisms directing bile canalicular transport of these agents will provide insights into the basis of their hepatic handling for assessing perturbations. Methods: We performed studies in animals, including healthy Fischer 344 rats or rats treated with carbon tetrachloride or intrasplenic cell transplantation and healthy Wistar rats or HsdAMC:TR-Abcc2 mutant rats in Wistar background. Onset of hepatic inflammation was verified by analysis of carbon uptake in Kupffer cells. Hepatic clearance of 99m Tc-mebrofenin was studied with dynamic imaging, and fractional retention of peak hepatic mebrofenin activity after 60 min was determined. Changes in the expression of bile canalicular transporters were analyzed by real-time polymerase chain reaction and Western blots. Results: Carbon tetrachloride and cell transplantation produced hepatic inflammation with activation of Kupffer cells, resulting in a rapid decline in the expression of the bile canalicular transporters Abcb4, Abcb11, and Abcc2. Among these transporters, decreased expression of Abcc2 was most prominent, and this decline persisted for 4 wk. Next, we examined 99m Tc-mebrofenin excretion in HsdAMC:TR-Abcc2 mutant rats (in which Abcc2 expression is naturally inactivated), compared with their healthy counterparts. In healthy HsdRccHan:WIST rats, only 23% 6 3% of the peak 99m Tc-mebrofenin activity was retained after 60 min. By contrast, in HsdAMC:TR-Abcc2 mutant rats, 73% 6 5% of the peak 99m Tc-mebrofenin activity was retained (P , 0.001). Moreover, the administration of cyclosporin A markedly inhibited 99m Tc-mebrofenin excretion in healthy rats, with no further effect on already impaired 99m Tc-mebrofenin excretion in HsdAMC:TR-Abcc2 mutant rats. Hepatic excretion of 99m Tc-mebrofenin was largely dependent on Abcc2. This molecular basis of 99m Tc-mebrofenin excretion will advance studies of pathophysiologic mechanisms in hepatic Abcc2 pathways.

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Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Cited by 23 publications

References 31 publications

Xenotransplantation of Hepatocytes in Rats with Acute Liver Failure Using Sirolimus for Immunosuppression

Xenotransplantation of Hepatocytes in Rats with Acute Liver Failure Using Sirolimus for Immunosuppression

Hepatocyte transplantation and drug-induced perturbations in liver cell compartments

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

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Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Cited by 23 publications

References 31 publications

Xenotransplantation of Hepatocytes in Rats with Acute Liver Failure Using Sirolimus for Immunosuppression

Xenotransplantation of Hepatocytes in Rats with Acute Liver Failure Using Sirolimus for Immunosuppression

Hepatocyte transplantation and drug-induced perturbations in liver cell compartments

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent 99mTc-Mebrofenin

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Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin