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      Oval Cells Contribute to Fibrogenesis of Marginal Liver Grafts under Stepwise Regulation of Aldose Reductase and Notch Signaling

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          Abstract

          Background and Aims: Expanded donor criteria poses increased risk for late phase complications such as fibrosis that lead to graft dysfunction in liver transplantation. There remains a need to elucidate the precise mechanisms of post-transplant liver damage in order to improve the long-term outcomes of marginal liver grafts. In this study, we aimed to examine the role of oval cells in fibrogenic development of marginal liver grafts and explore the underlying mechanisms.

          Methods: Using an orthotopic rat liver transplantation model and human post-transplant liver biopsy tissues, the dynamics of oval cells in marginal liver grafts was evaluated by the platform integrating immuno-labeling techniques and ultrastructure examination. Underlying mechanisms were further 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 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.

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          Most cited references 34

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          The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function.

          Podosomes and invadopodia are actin-based dynamic protrusions of the plasma membrane of metazoan cells that represent sites of attachment to - and degradation of - the extracellular matrix. The key proteins in these structures include the actin regulators cortactin and neural Wiskott-Aldrich syndrome protein (N-WASP), the adaptor proteins Tyr kinase substrate with four SH3 domains (TKS4) and Tyr kinase substrate with five SH3 domains (TKS5), and the metalloprotease membrane type 1 matrix metalloprotease (MT1MMP; also known as MMP14). Many cell types can produce these structures, including invasive cancer cells, vascular smooth muscle and endothelial cells, and immune cells such as macrophages and dendritic cells. Recently, progress has been made in our understanding of the regulatory and functional aspects of podosome and invadopodium biology and their role in human disease.
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            Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition.

            Activated fibroblasts are key contributors to the fibrotic extracellular matrix accumulation during liver fibrosis. The origin of such fibroblasts is still debated, although several studies point to stellate cells as the principal source. The role of adult hepatocytes as contributors to the accumulation of fibroblasts in the fibrotic liver is yet undetermined. Here, we provide evidence that the pro-fibrotic growth factor, TGF-beta1, induces adult mouse hepatocytes to undergo phenotypic and functional changes typical of epithelial to mesenchymal transition (EMT). We perform lineage-tracing experiments using AlbCre. R26RstoplacZ double transgenic mice to demonstrate that hepatocytes which undergo EMT contribute substantially to the population of FSP1-positive fibroblasts in CCL(4)-induced liver fibrosis. Furthermore, we demonstrate that bone morphogenic protein-7 (BMP7), a member of the TGFbeta superfamily, which is known to antagonize TGFbeta signaling, significantly inhibits progression of liver fibrosis in these mice. BMP7 treatment abolishes EMT-derived fibroblasts, suggesting that the therapeutic effect of BMP7 was at least partially due to the inhibition of EMT. These results provide direct evidence for the functional involvement of adult hepatocytes in the accumulation of activated fibroblasts in the fibrotic liver. Furthermore, our findings suggest that EMT is a promising therapeutic target for the attenuation of liver fibrosis.
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              The role and regulation of blebs in cell migration

               Ewa Paluch,  Erez Raz (2013)
              Blebs are cellular protrusions that have been shown to be instrumental for cell migration in development and disease. Bleb expansion is driven by hydrostatic pressure generated in the cytoplasm by the contractile actomyosin cortex. The mechanisms of bleb formation thus fundamentally differ from the actin polymerization-based mechanisms responsible for lamellipodia expansion. In this review, we summarize recent findings relevant for the mechanics of bleb formation and the underlying molecular pathways. We then review the processes involved in determining the type of protrusion formed by migrating cells, in particular in vivo, in the context of embryonic development. Finally, we discuss how cells utilize blebs for their forward movement in the presence or absence of strong substrate attachment.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2017
                24 October 2017
                : 7
                : 19
                : 4879-4893
                Affiliations
                [1 ]Department of Surgery, The University of Hong Kong, Hong Kong SAR, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, China;
                [2 ]School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China;
                [3 ]Department of Pathology, The University of Hong Kong, Hong Kong SAR, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China;
                [4 ]Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China;
                [5 ]Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong SAR, China.
                Author notes
                ✉ Corresponding author: Prof. Kwan Man; Address: L9-55, Department of Surgery, Lab Block, 21 Sassoon Road, Pokfulam, Hong Kong; Tel: 852-39179646; E-mail: kwanman@ 123456hku.hk ; Fax: 852-39179634

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov07p4879
                10.7150/thno.20085
                5706107
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

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