Thalidomide promotes transplanted cell engraftment in the rat liver by modulating inflammation and endothelial integrity

Background & Aims For liver-directed cell therapy, efficient engraftment of transplanted cells is critical. This study delineated whether anti-inflammatory and endothelial disrupting properties of thalidomide could promote transplanted cell engraftment and proliferation in liver. Methods We used dipeptidyl peptidase IV-deficient rats for cell transplantation studies, including gene expression analysis, morphological tissue analysis, serological assays, cell culture assays, and assays of transplanted cell engraftment and proliferation. Results Thalidomide-pretreatment increased engraftment and proliferation of transplanted hepatocytes due to decreased inflammation. Moreover, thalidomide exacerbated cell transplantation-induced endothelial injury. This combined anti-inflammatory and endothelial injury effect of thalidomide was superior to the anti-inflammatory effect alone of repertaxin or etanercept, which block cytokines/chemokines/receptor-dependent inflammation. In thalidomide-pretreated animals, liver repopulation accelerated, including when cells were primed with bosentan to block endothelin-1 receptors. Conclusions Thalidomide improved transplanted cell engraftment and liver repopulation. Therefore, this class of drugs will advance applications of liver cell therapy in people. Lay summary This work aimed to develop effective drug treatments for improving engraftment of transplanted cells because that constitutes a critical step in rebuilding liver with healthy cells. Studies in animal models of cell transplantation led to identification of an old drug, thalidomide, which blocked inflammation and altered the liver microenvironment to yield superior engraftment and proliferation of transplanted cells. This will be appropriate for liver cell therapy in people.