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Liver repopulation with bone marrow-derived cells improves the metabolic disorder in the Gunn rat
  1. Maurizio Muraca (muraca{at}opbg.net)
  1. Laboratory Medicien, Ospedale Bambino Gesù, Rome, Italy
    1. Chiara Ferraresso (ferraresso2{at}libero.it)
    1. Internal Medicine, University of Padova, Italy
      1. Maria Teresa Vilei (mariateresa.vilei{at}unipd.it)
      1. Internal Medicine, University of Padova, Italy
        1. Anna Granato (agranato{at}izsvenezie.it)
        1. Internal Medicine, University of Padova, Italy
          1. Mattia Quarta (mattiaq{at}tin.it)
          1. Internal Medicine, University of Padova, Italy
            1. Emanuele Cozzi (emanuele.cozzi{at}unipd.it)
            1. General Surgery, University of Padova, Italy
              1. Massimo Rugge (massimo.rugge{at}unipd.it)
              1. Pathology, IRCCS-IOV, University of Padova, Italy
                1. Karen Pauwelyn (karen_pauwelyn{at}hotmail.com)
                1. Internal Medicine, University of Leuven, Belgium
                  1. Maddalena Caruso (madda.caruso{at}gmail.com)
                  1. Laboratory Medicien, Ospedale Bambino Gesù, Rome, Italy
                    1. Itzhak Avital (avital{at}mskcc.org)
                    1. Memorial Sloane Kettering Cancer Centre, New York, United States
                      1. Daniel Inderbitzin (daniel.inderbitzin{at}insel.ch)
                      1. Transplantation and Abdominal Surgery, University of Bern, Switzerland
                        1. Achilles Demetriou (achilles.demetriou{at}uhhospitals.org)
                        1. Surgery, Cedars-Sinai Hospital, Los Angeles, Italy
                          1. Stuart Forbes (stuart.forbes{at}ed.ac.uk)
                          1. Centre for Inflammatory Research, University of Edinburgh, United Kingdom
                            1. Giuseppe Realdi (giuseppe.realdi{at}unipd.it)
                            1. Internal Medicine, University of Padova, Italy

                              Abstract

                              Background and aims: Reversible Ischemia/Reperfusion liver injury was used to induce engraftment and hepatic parenchymal differentiation of exogenous β2-microglubulin -/ Thy1+ bone marrow-derived cells. This method of hepatic parenchymal repopulation, theoretically applicable to clinical practice, was further tested to correct the metabolic disorder in a rat model of congenital hyperbilirubinemia. Methods and results: Analysis by confocal laser microscopy of fluorescence-labelled cells and by immunohistochemistry for β2-microglubulin, 72 hours after intraportal delivery, demonstrated engraftment of infused cells in liver parenchyma of rats with Ischemia/Reperfusion, but not in control animals with non-injured liver. Transplantation of bone marrow-derived cells obtained from GFP-transgenic rats into Lewis rats resulted in the presence of up to 20% of GFP-positive hepatocytes in Ischemia/Reperfusion liver lobes after one month. The repopulation rate was proportional to the number of transplanted cells. Infusion of GFP-negative bone marrow-derived cells into GFP-positive transgenic rats resulted in the appearance of GFP-negative hepatocytes, suggesting that the main mechanism underlying parenchymal repopulation was differentiation rather than cell fusion. Transplantation of wild type bone marrow-derived cells into hyperbilirubinemic Gunn rats with deficient bilirubin conjugation after Ischemia/Reperfusion damage resulted in 30% decrease of serum bilirubin, in the appearance of bilirubin conjugates in bile and in the expression of normal UDP-glucuronyltransferase enzyme evaluated by PCR. Conclusions: Ischemia/Reperfusion injury induced hepatic parenchymal engraftment and differentiation into hepatocyte-like cells of bone marrow-derived cells. Transplantation of bone marrow-derived cells from non-affected animals resulted in the partial correction of hyperbilirubinemia in the Gunn rat.

                              • crigler-najjar disease
                              • green fluorescent protein
                              • ischemia-reperfusion
                              • liver regeneration
                              • beta-2-microglobulin

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