Studies on the Safety of Intrasplenic Hepatocyte Transplantation: Relevance to<i>Ex Vivo</i>Gene Therapy and Liver Repopulation in Acute Hepatic Failure

Gupta, Sanjeev; Yerneni, Purnachandra R.; Vemuru, Ravikumar; Lee, Chang Don; Yellin, Edward L.; Bhargava, Kuldeep K.

doi:10.1089/hum.1993.4.3-249

Cited by 80 publications

(61 citation statements)

References 31 publications

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“…1 These diseases are attractive targets for hepatocyte transplantation or gene transfer into hepatocytes. Hepatocyte transplantation has been performed in animal models [2][3][4] as well as limited human clinical trials, 5,6 but only Ͻ1% of the hepatocyte mass could be replaced. This has resulted in poor clinical efficacy of the procedure.…”

Section: Recent Work Has Convincingly Demonstrated That Adult Bone Mamentioning

confidence: 99%

Kinetics of Liver Repopulation after Bone Marrow Transplantation

Wang

Montini

Al‐Dhalimy

et al. 2002

The American Journal of Pathology

225

197

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Recent work has convincingly demonstrated that adult bone marrow contains cells capable of differentiating into liver epithelial cells in vivo. However, the frequency and time course with which fully functional hepatocytes emerge after bone marrow transplantation remained controversial. Here, we used the fumarylacetoacetate hydrolase knockout mouse to determine the kinetics of hepatocyte replacement after complete hematopoietic reconstitution. Single donorderived hepatocytes were first detected 7 weeks after lethal irradiation and bone marrow transplantation. Liver disease was not required for this transdifferentiation. In the presence of selective pressure the single cells evolved into hepatocyte nodules by 11 weeks after transplantation and resulted in >30% overall liver repopulation by 22 weeks. The frequency with which hepatocytes were produced was between 10 ؊4 and 10 ؊6 , resulting in only 50 to 500 repopulation events per liver. Hepatic engraftment was not observed without previous hematopoietic reconstitution even in the presence of liver injury. In addition, significant liver repopulation was completely dependent on hepatocyte growth selection. We conclude that hepatocyte replacement by bone marrow cells is a slow and rare event. Significant improvements in the efficiency of this process will be needed before clinical success can be expected.

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Section: Recent Work Has Convincingly Demonstrated That Adult Bone Mamentioning

confidence: 99%

Kinetics of Liver Repopulation after Bone Marrow Transplantation

Wang

Montini

Al‐Dhalimy

et al. 2002

The American Journal of Pathology

225

197

View full text Add to dashboard Cite

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“…Previous studies showed that severe portal hypertension develops during cell injection into the spleen, although after several weeks portal pressures, as well as angiographic appearances of the portal circulations, were normal in recipients. 14 To document the kinetics of this change in portal pressures, we transplanted 2 ϫ 10 7 or 7.5 ϫ 10 7 hepatocytes in groups of three rats each. Interestingly, portal pressures were normal in all animals after 1, 3, 7, and 10 days of cell transplantation.…”

Section: Hemodynamic Consequences Of Cell Translocations and Entry Intomentioning

confidence: 99%

“…We further analyzed the process by which portal hypertension induced by intrasplenic cell transplantation is resolved. 14 The hypothesis was that, on translocation of transplanted cells from the hepatic sinusoids and integrations in liver plates, changes in the portal vascular bed will resolve as the hepatic circulation is restored. Finally, we investigated whether specific factors, such as the vascular endothelial growth factor (VEGF), which is also known as vascular permeability factor (VPF), was released during cell engraftment.…”

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confidence: 99%

Entry and Integration of Transplanted Hepatocytes in Rat Liver Plates Occur by Disruption of Hepatic Sinusoidal Endothelium

et al. 1999

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To establish the process by which transplanted cells integrate into the liver parenchyma, we used dipeptidyl peptidase IV-deficient F344 rats as hosts. On intrasplenic injection, transplanted hepatocytes immediately entered liver sinusoids, along with attenuation of portal vein radicles on angiography. However, a large fraction of transplanted cells (Ͼ70%) was rapidly cleared from portal spaces by phagocyte/macrophage responses. On the other hand, transplanted hepatocytes entering the hepatic sinusoids showed superior survival. These cells translocated from sinusoids into liver plates between 16 and 20 hours after transplantation, during which electron microscopy showed disruption of the sinusoidal endothelium. Interestingly, production of vascular endothelial growth factor was observed in hepatocytes before endothelial disruptions. Portal hypertension and angiographic changes resulting from cell transplantation resolved promptly. Integration of transplanted hepatocytes in the liver parenchyma required cell membrane regenesis, with hybrid gap junctions and bile canaliculi forming over 3 to 7 days after cell transplantation. We propose that strategies to deposit cells into distal hepatic sinusoids, to disrupt sinusoidal endothelium for facilitating cell entry into liver plates, and to accelerate cell integrations into liver parenchyma will advance applications of hepatocyte transplantation. (HEPATOLOGY 1999;29:509-519.)

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“…10,11 functional support of chronic hepatic failure and congenital It has been reported that a PH of 70% stimulated DNA metabolic disorders, the long-term survival of a large number synthesis of intrasplenically transplanted hepatocytes, but no of transplanted hepatocytes in ectopic sites or the liver of increase in the number of surviving hepatocytes was found. 15,16 The stimulative effect of a PH of 70% might be rapidly utilized by the remnant liver and did not affect the proliferation of intrasplenically transplanted hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Functional assessment of proliferating hepatocytes stimulated by hepatic stimulatory substance in ascorbic acid biosynthetic enzyme-deficient rats

et al. 1997

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the possibility of metabolic support by HTx for animals with The functional ability of hepatic stimulatory substance congenital metabolic disorders. 1 We have already reported (HSS)-stimulated proliferating hepatocytes was investigated that transplanted syngeneic hepatocytes survived in the by intrasplenic and/or intraportal transplantation in ascorbic spleen for a long time, recomposing hepatic cord structure, acid (AsA) biosynthetic enzyme-deficient (ODS-od/od) rats and that they exhibited hepatocellular function by histothat die of osteogenic disorders unless there is AsA supplechemical study.2 However, the time required for transplanted mentation. HSS was extracted from regenerating porcine livhepatocytes to exhibit sufficient hepatocellular function is ers. Hepatocytes isolated from the livers of congeneic ODStoo long for this modality to be used in experimental models /// rats that are capable of synthesizing AsA were of chronic hepatic failure and congenital metabolic disortransplanted into the spleen (Sp-HTx) and/or the portal vein (Pv-HTx) of ODS-od/od rats. The recipients were divided into ders. The ODS-od/od rat is unable to synthesize ascorbic acid sham-operated, HTx(0); group IIa, Sp-HTx; group IIIa, Pv-(AsA) because of a congenital lack of L-gulonolactone oxidase HTx; and group IVa, Sp-and Pv-HTx], HSS-treated groups in the liver and dies of osteogenic disorders following severe [group Ib, HSS only; group IIb, Sp-HTx / HSS; group IIIb, weight loss and bleeding unless they are given exogenous Pv-HTx / HSS; and group IVb, Sp-and Pv-HTx / HSS]. The AsA.3 Congeneic HTx into the spleen and the portal vein recipients were given a diet and water containing AsA for 6 improved the survival rate of ODS-od/od rats when the recipiweeks after HTx, and AsA supplementation was then halted. ent rats were pretreated with a hepatotoxin, 2-acetylThe average bromodeoxyuridine (BrdU) labeling index (LI) aminofluorene, and a subsequent partial hepatectomy (PH) and hepatocyte-occupied ratio in the spleen (H/S ratio) of of 70%. 4 However, this pretreatment and PH cannot be ap-HSS-treated rats were significantly higher than those of HSS-plied in patients with hepatic disorders. Therefore, a method untreated rats. All the rats in HSS-untreated groups and group of inducing immediate and rapid proliferation of transplanted Ib died by 8 weeks after the cessation of AsA. In HSS-treated hepatocytes is urgently needed. groups IIb, IIIb, and IVb, the survival rates were 60%, 50%, Hepatic stimulatory substance (HSS), which can be exand 80%, respectively, at 16 weeks after HTx. The average tracted from fetal, weanling, and regenerating livers, stimuserum AsA level of the surviving rats in groups IIb, IIIb, lates liver regeneration after PH and the proliferation of culand IVb was significantly higher than that in HSS-untreated tured hepatocytes. 5 We have already confirmed the beneficial groups. These results indicate that HSS treatment induced effect of HSS on the survival of intrasplenically transplanted rapid proliferation of tran...

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Studies on the Safety of Intrasplenic Hepatocyte Transplantation: Relevance toEx VivoGene Therapy and Liver Repopulation in Acute Hepatic Failure

Cited by 80 publications

References 31 publications

Kinetics of Liver Repopulation after Bone Marrow Transplantation

Kinetics of Liver Repopulation after Bone Marrow Transplantation

Entry and Integration of Transplanted Hepatocytes in Rat Liver Plates Occur by Disruption of Hepatic Sinusoidal Endothelium

Functional assessment of proliferating hepatocytes stimulated by hepatic stimulatory substance in ascorbic acid biosynthetic enzyme-deficient rats

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