gms | German Medical Science

Introduction: Hepatocyte transplantation is strongly considered to be a promising option to correct chronic liver failure through repopulation of the diseased organ. We already reported on extensive liver repopulation by hepatocytes transplanted into rats preconditioned with 25 Gy single dose selective external beam irradiation (IR). With respect to clinical use, we tested the applicability of lower radiation doses and fractionated protocols in this study.

Materials and methods: Livers of dipeptidylpeptidase IV (DPPIV)-deficient rats were pre-conditioned with partial liver external beam single dose IR at 25 Gy, 8 Gy, or 5 Gy, or fractionated IR at 5x5 Gy or 5x2 Gy. Four days following completion of IR, a partial hepatectomy (PH) was performed to resect the untreated liver section. Subsequently, 12 million wild-type (DPPIV⁺) hepatocytes were transplanted via the spleen into the recipient livers. The degree of donor cell integration and liver repopulation was studied 16 weeks after transplantation by means of immunofluorescence and DPPIV-luminescence assay.

Results: Donor hepatocyte integration and liver repopulation were more effective in the irradiated livers following pre-treatment with the IR doses 1x25 Gy and 5x5 Gy (formation of large DPPIV-positive cell clusters) than single dose irradiation at 8 Gy or 5 Gy (DPPIV-positive clusters noticeably smaller and less frequent). Quantitative analysis of extracted DPPIV revealed signals exceeding the control level in all transplanted animals treated with IR and PH. Compared to the standard treatment of 1x25 Gy, fractionation with 5x5 Gy was equally efficacious, the Mann Whitney-U Test disclosing no statistically significant difference (p=0,146). The lower doses of 1x5 Gy, 1x8 Gy and 5x2 Gy were significantly less effective with p<0,05.

Conclusion: This study suggests that fractionated radiotherapy in combination with PH is an effective pre-treatment approach to prime the host liver for hepatocyte transplantation, thus bringing the experimental model a step closer to clinical application.