And these oval cells differentiated mainly along biliary lineage during tissue repair

And these oval cells differentiated mainly along biliary lineage during tissue repair. Activation of aldose reductase triggered oval cell proliferation Our recent study Asunaprevir (BMS-650032) reported that Aldose reductase (AR) was a major player in inflammation induced graft injury 12. explored in oval cells and an Aldose reductase (AR) knockout mouse model simulating marginal graft injury. Results: We demonstrated that activation of aldose reductase initiated oval cell proliferation in small-for-size fatty grafts during ductular reaction at the early phase after transplantation. These proliferative oval cells subsequently showed prevailing biliary differentiation and exhibited features of mesenchymal transition including dynamically co-expressing epithelial and mesenchymal markers, developing microstructures for extra-cellular matrix degradation (podosomes) or cell migration (filopodia and blebs), and acquiring the capacity in collagen production. Mechanistic studies further indicated that transition of oval cell-derived biliary cells toward mesenchymal phenotype ensued fibrogenesis in marginal grafts under the regulation of notch signaling Asunaprevir (BMS-650032) pathway. Conclusions: Oval cell activation and their subsequent lineage commitment contribute to post-transplant fibrogenesis of small-for-size fatty liver grafts. Interventions targeting oval cell dynamics may serve as potential strategies to refine current clinical management. strong class=”kwd-title” Keywords: hepatic bipotent cells, small-for-size fatty graft injury, aldose reductase, notch signaling. Introduction With the ever increasing demand on liver transplantation, marginal liver grafts Asunaprevir (BMS-650032) such as small-for-size and/or fatty grafts have been adopted to expand the liver donor pool in recent years. Yet it has been long noted that marginal liver grafts in living donor liver transplantation (LDLT) are more susceptible to insults such as ischemia reperfusion (I/R) injury and viral infection after transplantation 1, 2, which result in worse graft function and survival 3, 4. Post-transplant fibrosis is a common reason for late-phase graft dysfunction in liver transplantation 5, 6. Increasing data have demonstrated the strong association between activation of hepatic bipotent progenitor cells (oval cells) and fibrogenesis 7, 8. Some recent studies also suggested that oval cells may contribute to liver fibrosis by serving as a source of myofibroblasts 9, 10. However, the direct participation of oval cells in liver graft fibrosis remains undefined, especially in terms of how oval cells are initiated and terminated into extracelluar matrix (ECM)-producing cells in marginal liver grafts. Liver transplant procedure with its related ischemia/reperfusion (I/R) injury and the DEPC-1 surgical trauma resulted in inflammation detrimental to allograft function 11. Our recent study showed that Aldose reductase (AR), a polyol pathway enzyme traditionally believed to play essential roles in glucose metabolism and detoxification of a wide range of aldehydes, was a critical responsive gene to inflammation after liver transplantation 12 . Study from other research group also reported that AR affected the development of diet-induced liver steatosis 13. Nevertheless, the cross-talk between AR and oval cells in fibrogenic development in marginal grafts has not been explored so far. Epithelial-to-Mesenchymal transition (EMT) is a critical physio-pathological phenomenon observed either in embryonic development, fibrosis or cancer progression. In latest Asunaprevir (BMS-650032) years, there has been increasing interest in the role of EMT in fibrogenesis during chronic liver diseases 7, 14-16. Yet whether certain types of liver cells such as biliary cells are capable of undergoing EMT in liver injury remained controversial 16-19. Meanwhile, morphological evidence supporting the presence of transition was scarce. In this study, with an orthotopic rat liver transplantation model mimicking marginal graft injuries encountered in human living donor liver transplantation, we demonstrated that aldose reductase triggered oval cell proliferation during the early phase after transplantation. Following acquisition of biliary differentiation in the mid-late phase, these progenitor cells contributed to graft fibrogenesis via mesenchymal transition, which was regulated by notch signaling pathway. Materials and Methods Experimental design The study consisted of three parts. In part I, post-transplant oval cell activation in marginal liver grafts was evaluated in an orthotopic rat liver transplantation model simulating clinical living donor liver transplantation. Then lineage commitment.