Efficacy and safety of repeated hepatocyte transplantation for significant liver repopulation in rodents

Rajvanshi, Pankaj; Kerr, Andrew; Bhargava, Kuldeep K.; Burk, RD; Gupta, Sanjeev

doi:10.1016/s0016-5085(96)70078-1

Cited by 110 publications

(89 citation statements)

References 3 publications

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“…36 To illustrate, the liver of rats treated with retrorsine-PH is repopulated in 12 weeks. 7 If transplantation of 2 ϫ 10 7 cells repopulates 1.5% of the liver, 23 6 transplanted cell mass doublings will be needed over 12 weeks for 100% liver repopulation, with each doubling requiring 2 weeks, assuming a constant rate of transplanted cell proliferation. Each increase in original transplanted cell mass should curtail cell doublings needed for achieving a given magnitude of liver repopulation.…”

Section: Discussionmentioning

confidence: 99%

Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver

et al. 2002

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To determine whether disruption of the hepatic sinusoidal endothelium will facilitate engraftment of transplanted cells, we treated Fischer 344 (F344) rats lacking dipeptidyl peptidase IV (DPPIV) activity with cyclophosphamide (CP). Electron microscopy showed endothelial injury within 6 hours following CP, and, after 24 and 48 hours, the endothelium was disrupted in most hepatic sinusoids. CP did not affect Kupffer cell function. Similarly, CP had no obvious effects on hepatocytes. Intrasplenic transplantation of F344 rat hepatocytes followed by their localization with DPPIV histochemistry showed 3-to 5-fold increases in the number of transplanted cells in CP-treated animals. Transplanted cells integrated in the liver parenchyma more rapidly in CPtreated animals, and hybrid bile canaliculi developed even 1 day after cell transplantation, which was not observed in control animals. To demonstrate whether improved cell engraftment translated into superior liver repopulation, recipient animals were conditioned with retrorsine and two-thirds partial hepatectomy (PH), which induces transplanted cell proliferation. CP treatment of these animals before cell transplantation significantly increased the number and size of transplanted cell foci. In conclusion, disruption of the hepatic sinusoidal endothelium was associated with accelerated entry and integration of transplanted cells in the liver parenchyma. These results provide insights into hepatocyte engraftment in the liver and will help in optimizing liver-directed cell therapy. ( T ransplanted hepatocytes integrate in the liver, survive throughout the life of animals, and express genes normally. 1-3 However, several days are required for transplanted cells to integrate in the liver parenchyma. 4 Moreover, transplanted cells do not proliferate significantly in the normal adult liver, 3 although, when proliferation and/or survival of native and transplanted cells are dissociated, transplanted hepatocytes can repopulate the liver extensively. [5][6][7][8][9][10] The possibility of therapeutic liver repopulation has been tested in several animal models with liver failure, genetic diseases, and metabolic deficiency states. [11][12][13][14] The swiftness with which transplanted cells engraft could be critical for liver repopulation. After injection into the portal system, transplanted cells lodge in hepatic sinusoids because of differences in the dimensions of these cells and sinusoids. 15 This is associated with changes in native hepatocytes, such as gamma-glutamyl transpeptidase activation and disruption of gap junctions. 16 The sinusoidal endothelium is disrupted 16 to 20 hours after transplantation, which provides transplanted cells access to the space of Disse. 4 Transplanted cells then translocate into the liver plate, with reconstitution of gap junctions and bile canaliculi over 3 to 7 days. However, delays in cell engraftment affect transplanted cell proliferation. In rats subjected to two-thirds partial hepatectomy (PH), which induces hepatic DNA synthesis within ...

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Section: Discussionmentioning

confidence: 99%

Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver

et al. 2002

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“…After hepatocyte transplantation, recipient animals were killed at 2, 4,6,8,12,16,20, and 24 hours, and at 2, 3, 4, and 7 days for tissue analysis. These animals received 2 ϫ 10 7 hepatocytes via the spleen.…”

Section: Methodsmentioning

confidence: 99%

“…1E and F). The analysis of tissues obtained at 4,6,8,12,16, and 20 hours after cell transplantation showed that hepatocytes entered host liver plates between 16 to 20 hours after transplantation. Before 16 hours, transplanted cells could be readily seen in hepatic sinusoids.…”

Section: Kinetics Of Hepatocyte Translocations Into Livermentioning

confidence: 99%

“…[3][4][5] Previous studies documented that transplanted hepatocytes can integrate into the host liver parenchyma. [6][7][8] In the presence of chronically sustained hepatocyte losses, e.g., the uPA transgenic mouse, which expresses a hepatocyte-lethal transgene, 9 and the Fah ⌬exon5 mouse, which is a model of hereditary tyrosinemia type 1, 10 transplantation of normal hepatocytes leads to extensive liver repopulation. Although engraftment of relatively few clonogenic cell populations may be adequate for liver repopulation in such situations, in other circumstances, transplantation of larger numbers of cells will be necessary.…”

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confidence: 99%

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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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“…Since hepatocyte transplantation is not deleterious for the recipient liver, repeated cell infusions could be safely performed and were effective in increasing the extent of liver repopulation. 82 Engraftment of transplanted hepatocytes has been shown to be significantly higher in animals that have been subjected to partial hepatectomy or portal ligature before cell infusion. This higher efficacy probably reflects the favorable environment in regenerating livers (vascular remodelling, secretion of growth factors and cytokines, such as hepatocyte growth factor and VEGF).…”

Section: Strategies For Liver Repopulationmentioning

confidence: 99%

Liver gene therapy: advances and hurdles

Nguyen

Ferry

2004

Gene Ther

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Efficacy and safety of repeated hepatocyte transplantation for significant liver repopulation in rodents

Cited by 110 publications

References 3 publications

Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver

Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver

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

Liver gene therapy: advances and hurdles

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