Can Hepatocytes Proliferate when Transplanted into the Spleen?

Nordlinger, Bernard; Wang, S.R.; Bouma, M.E.; Verthier, Nicole; Hillan, Kenneth J.; Delelo, R; Infante, R

doi:10.1159/000128726

Cited by 22 publications

(5 citation statements)

References 8 publications

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“…Although several previous studies (reviewed in refs. 1 and 2) have used histological techniques to demonstrate hepatocyte-like cells within the spleen (3)(4)(5)(6)(7)(8)(9)(10)(11)(12), fat pads (13), pancreas (14,15), or subrenal capsule (16), or on microcarrier beads in the peritoneum (17), after hepatocyte injections, the number of surviving cells and their degree of liver function have been impossible to assess due to the absence of quantitative biochemical markers and/or rejection of transplanted cells. Short-term (4,(17)(18)(19)(20) or long-term (3,14) reconstitution of some hepatic function has been demonstrated by transplanting normal hepatocytes into rats with a genetic deficiency of uridine diphosphate (UDP)-glucuronyltransferase, but it is unclear how many surviving hepatocytes were required to produce the slight decrease in serum bilirubin and increase in conjugated bilirubin in the bile.…”

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confidence: 99%

Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation.

Ponder

Gupta

Leland

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

353

196

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One approach to gene therapy for hepatic diseass is to remove hepatocytes from an affected individual, genetically alter them in vitro, and reimplant them into a receptive locus. Although returning hepatocytes to the liver itself would be advantageous, the feasibility of this approach has never been evaluated due to the inability to distinguish donor from host hepatocytes. To unambiguously identify transplanted hepatocytes after transplantation, and to better quantitate their number and degree of liver function, two transgenic mouse lines were generated in a C57BL/6 background. The first expresses the Escherichia cofi p-galactosidase gene from the relatively liver-specific human a1-antitrypsin (hAAT) promoter and allows transgenic hepatocytes to be readily identified after 5-bromo-4-chloro-3-indolyl .8-D-galactoside staining; the second produces the hAAT protein under control of the same promoter, which enables hepatocyte survival and maintenance of liver function to be quantitated by measuring the serum levels of hAAT. Hepatocytes isolated from transgenic donors were transplanted into nontransgenic C57BL/6 recipients by intrasplenic injection. Surprisingly, a large fraction of these cells were identified within the liver parenchyma but not the spleen at 2 months after transplantation. The high levels of serum hAAT detected in transplant recipients were stable for >6 months, suggesting that established cells will survive indefinitely. These results have important implications for liver organogenesis and hepatic gene therapy.

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mentioning

confidence: 99%

Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation.

Ponder

Gupta

Leland

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

353

196

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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. We previously investigated the efficacy of intrasplenic and intraportal HTx in ODS-od/od rats.…”

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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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“…The proliferative activity of intrasplenic adult hepatocytes has been evaluated by [H3]-thymidine labeling [17] and bromodeoxyuridine (BrdU) labeling indices [3]. Monoclonal antibodies have recently been developed against PCNA, an auxiliary factor for the DNA polymerase 8 [8].…”

Section: Discussionmentioning

confidence: 99%

Long-term effects of intrasplenically transplanted adult hepatocytes and fetal liver in hyperbilirubinemic Gunn rats

et al. 1995

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We performed adult hepatocyte transplantation (HCTx) and fetal liver transplantation (FLTx) into the spleens of hyperbilirubinemic Gunn rats in congenic combination and we compared the long-term effects of these procedures for as long as 12 months. Proliferative activity of intrasplenic hepatocytes was evaluated using antiproliferating cell nuclear antigen (PCNA) immunohistochemical staining. The serum total bilirubin levels (T. Bil) significantly decreased from 7.16 +/- 0.25 mg/dl to 4.38 +/- 0.60 mg/dl 2 months after HCTx and gradually decreased thereafter until 12 months after transplantation (3.23 +/- 0.37 mg/dl, P < 0.05 vs preoperative value). The T. Bil change after FLTx was similar to that of HCTx: 7.22 +/- 0.24 mg/dl before FLTx, and 4.92 +/- 0.24 and 3.06 +/- 0.47 mg/dl, 2 and 12 months after FLTx (P < 0.05), respectively. Bilirubin glucuronides, which were not detectable in the bile from untreated Gunn rats, appeared in considerable amounts 4 months after HCTx and FLTx (27.5% and 36.0% of total bile, respectively). PCNA labeling indices of intrasplenic hepatocytes (4.9% +/- 0.9% and 3.7% +/- 0.7%, 6 months after HCTx and FLTx, respectively) were slightly higher than those of normal hepatocytes (1.0% +/- 0.1%) in the host liver. In conclusion, both adult and fetal rat hepatocytes transplanted into the spleen in congenic combination functioned for at least a year in terms of bilirubin glucuronidation. The spleen is considered to be one of the optimal grafting sites for hepatocytes, with nearly lifelong significant function and proliferative activity.

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Can Hepatocytes Proliferate when Transplanted into the Spleen?

Cited by 22 publications

References 8 publications

Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation.

Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation.

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

Long-term effects of intrasplenically transplanted adult hepatocytes and fetal liver in hyperbilirubinemic Gunn rats

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