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Abstract

Despite progress in the field of immunosuppression, acute rejection is still a common postoperative complication following liver transplantation. This study aims to investigate the capacity of the human hepatocyte growth factor (hHGF) in modifying hepatic oval cells (HOCs) administered simultaneously with orthotopic liver transplantation as a means of improving graft survival. HOCs were activated and isolated using a modified 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) model in male Lewis rats. A HOC line stably expressing the HGF gene was established following stable transfection of the pBLAST2-hHGF plasmid. Our results demonstrated that hHGF-modified HOCs could efficiently differentiate into hepatocytes and bile duct epithelial cells in vitro. Administration of HOCs at the time of liver transplantation induced a wider distribution of SRY-positive donor cells in liver tissues. Administration of hHGF-HOC at the time of transplantation remarkably prolonged the median survival time and improved liver function for recipients compared to these parameters in the other treatment groups (P<0.05). Moreover, hHGF-HOC administration at the time of liver transplantation significantly suppressed elevation of interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) levels while increasing the production of IL-10 and TGF-β1 (P<0.05). HOC or hHGF-HOC administration promoted cell proliferation, reduced cell apoptosis, and decreased liver allograft rejection rates. Furthermore, hHGF-modified HOCs more efficiently reduced acute allograft rejection (P<0.05 versus HOC transplantation only). Our results indicate that the combination of hHGF-modified HOCs with liver transplantation decreased host anti-graft immune responses resulting in a reduction of allograft rejection rates and prolonging graft survival in recipient rats. This suggests that HOC-based cell transplantation therapies can be developed as a means of treating severe liver injuries.

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Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. hHGF-modified HOC differentiation potential.

LIF…

Figure 1. hHGF-modified HOC differentiation potential.

LIF was withdrawn from culture medium to induce cell…

Figure 1. hHGF-modified HOC differentiation potential. LIF was withdrawn from culture medium to induce cell differentiation. (A) Intracellular hHGF protein expression was determined by Western blot analysis. hHGF was used as positive control and β-actin used as an internal control. (B) Undifferentiated or differentiated normal HOCs or hHGF-modified HOCs were monitored under phase contrast microscopy. Arrows indicated long-spindle like bile duct epithelial cells and arrowheads indicat the large, round-shaped hepatocytes. (C) Immunostaining of differentiated cells with specific antibodies for ALB or CK19. Arrows indicated immuno-positive cells (dark brown cells). Sections were double-stained with H&E. Magnification ×200.
Figure 2

Figure 2. Experimental design outline.

Figure 2. Experimental design outline.

Figure 2. Experimental design outline.
Figure 3

Figure 3. In situ hybridization of SRY-positive…

Figure 3. In situ hybridization of SRY-positive donor HOCs.

In situ hybridization was performed 21…
Figure 3. In situ hybridization of SRY-positive donor HOCs. In situ hybridization was performed 21 days post transplantation. Ovarian tissue was used as a negative control and renal tissues from male Lewis rats used as positive controls. SRY-positive cells exhibited dark brown staining of their nuclei and/or cytoplasm. Following HOC administration to liver transplant recipients, SRY-positive cells were found in liver tissues and hepatic sinusoids. Additionally, SRY-positive hHGF-HOCs were observed in the surrounding portal area, central vein and bile duct, and were diffusely distributed in hepatic lobules. Magnification is indicated on each image.
Figure 4

Figure 4. Analysis of serum cytokine levels…

Figure 4. Analysis of serum cytokine levels post transplantation.

Serum IL-2, IL-10, TNF-α, TGF-β1, and…

Figure 4. Analysis of serum cytokine levels post transplantation. Serum IL-2, IL-10, TNF-α, TGF-β1, and IFN-γ levels were examined at the indicated time points post transplantation by ELISA. Differences were analyzed using an analysis of variance or an independent sample t-test. *P<0.05, liver transplantation only vs. hHGF-HOC+liver transplantation or HOC+liver transplantation vs. hHGF-HOC+liver transplantation; #P<0.05, liver transplantation vs. HOC+liver transplantation.
Figure 5

Figure 5. Survival curves of recipients.

Figure 5. Survival curves of recipients.

Figure 5. Survival curves of recipients.
Figure 6

Figure 6. Cell proliferation and apoptosis.

The…

Figure 6. Cell proliferation and apoptosis.

The beneficial effects of hHGF-HOCs on liver transplantation were…

Figure 6. Cell proliferation and apoptosis. The beneficial effects of hHGF-HOCs on liver transplantation were evaluated by measuring cell proliferation and apoptosis. (A) Fourteen days post-transplantation, tissue sections were stained with specific antibodies to PCNA. Arrows indicated immuno-positive cells. Magnification ×100. (B) The protein expression of NFκB was examined by Western blot analysis.
Figure 7

Figure 7. Histological examination of liver allograft…

Figure 7. Histological examination of liver allograft rejection.

(A) Sections obtained from experimental groups were…

Figure 7. Histological examination of liver allograft rejection. (A) Sections obtained from experimental groups were staining with H&E, magnification ×100. (B) Liver allograft rejection was assessed using the rejection activity index according to the Banff classification of hepatic allograft rejection described in the Materials and Methods. Data were compared with analysis of variance or an independent sample t-test. *P<0.05 liver transplantation vs. hHGF-HOC+liver transplantation or HOC+liver transplantation vs. hHGF-HOC+liver transplantation; #P<0.05, liver transplantation vs. HOC+liver transplantation.
Figure 8

Figure 8. Immunostaining for ICAM-1, Fas, CD44…

Figure 8. Immunostaining for ICAM-1, Fas, CD44 and CD40 28 days post transplantation.

Immunopositive cells…

Figure 8. Immunostaining for ICAM-1, Fas, CD44 and CD40 28 days post transplantation. Immunopositive cells exhibited dark-brown staining. Sections were double stained with H&E (blue). Magnification is indicated on each image.
All figures (8) See this image and copyright information in PMC

References

    1. Kaufman DB, Shapiro R, Lucey MR, Cherikh WS, R TB, et al. (2004) Immunosuppression: practice and trends. Am J Transplant 4 Suppl 9: 38–53. - PubMed
    1. Knechtle SJ, Kwun J (2009) Unique aspects of rejection and tolerance in liver transplantation. Semin Liver Dis 29: 91–101. - PubMed
    1. Tosh D, Strain A (2005) Liver stem cells–prospects for clinical use. J Hepatol 42 Suppl: S75–84. - PubMed
    1. Faris RA, Konkin T, Halpert G (2001) Liver stem cells: a potential source of hepatocytes for the treatment of human liver disease. Artif Organs 25: 513–521. - PubMed
    1. Fausto N, Campbell JS (2003) The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 120: 117–130. - PubMed
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