Prolonged survival by combined treatment with granulocyte colony-stimulating factor and dipeptidyl peptidase IV inhibitor in a rat small-for-size liver transplantation model

Aim: Despite the great advances and excellent outcomes of liver transplantation (LT), small-for-size (SFS) graft syndrome is a life-threatening complication that remains to be overcome. In the present study, we investigated the therapeutic effect of combined treatment with granulocyte colony-stimulating factor (G-CSF) and a dipeptidyl peptidase IV (DPP-IV) inhibitor on SFS liver graft syndrome. Methods: The transplantation of small-sized Lewis donor livers into green fluorescent protein (GFP) transgenic Wistar rats was performed and the recipients were randomly assigned to one of four groups (without treatment, DPP-IV inhibitor treatment, G-CSF treatment and G-CSF/DPP-IV inhibitor combination). Recombinant human G-CSF was injected s.c. at a dose of 2μg/kg per day starting 5 days prior to transplantation. G-CSF was combined with the p.o. administration of a DPP-IV inhibitor (2mg/kg per day) after transplantation until the end of the observation period. Results: The post-transplant survival and liver function of rats treated with G-CSF/DPP-IV inhibitor combination therapy were significantly improved with an increased number of recipient-derived GFP positive cells into the liver grafts. A confocal microscopy study showed cytokeratin (CK)-18 and GFP positive hepatic progenitor cells in the parenchyma of the liver allografts. Untreated rats and rats treated with either G-CSF or DPP-IV inhibitor did not exhibit the prolonged survival and had less GFP and CK-18 positive cells in the liver grafts after SFS LT. Conclusion: Our results suggest that combined treatment with G-CSF and DPP-IV inhibitor may synergistically induce migration and differentiation of recipient-derived stem cells into the hepatic progenitor cells, resulting in the amelioration of SFS liver graft syndrome.