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Liver repopulation with bone marrow derived cells improves the metabolic disorder in the Gunn rat
  1. M Muraca1,
  2. C Ferraresso2,
  3. M T Vilei2,
  4. A Granato2,
  5. M Quarta2,
  6. E Cozzi3,
  7. M Rugge4,
  8. K A Pauwelyn5,
  9. M Caruso1,
  10. I Avital6,
  11. D Inderbitzin7,
  12. A A Demetriou8,
  13. S J Forbes9,
  14. G Realdi2
  1. 1
    Ospedale Bambino Gesù, Laboratory Medicine, Rome, Italy
  2. 2
    University of Padova, Internal Medicine, Padova, Italy
  3. 3
    University of Padova, Surgery, Padova, Italy
  4. 4
    IRCCS-IOV University of Padova, Pathology, Padova, Italy
  5. 5
    Catholic University of Leuven, Internal Medicine, Leuven, Belgium
  6. 6
    Memorial-Sloan Kettering Cancer Center, Surgery, New York, USA
  7. 7
    University of Bern, Transplantation and Abdominal Surgery, Bern, Switzerland
  8. 8
    Cedars-Sinai Medical Center, Surgery, Los Angeles, USA
  9. 9
    The Tissue Fibrosis and Repair Laboratory MRC/University of Edinburgh Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh, UK
  1. Professor Maurizio Muraca, Responsabile del Laboratorio Analisi, Ospedale Pediatrico Bambino Gesù, Piazza Sant’Onofrio 4, 00165 Roma; muraca{at}opbg.net

Abstract

Background: Reversible ischaemia/reperfusion (I/R) liver injury has been used to induce engraftment and hepatic parenchymal differentiation of exogenous β2-microglubulin/Thy1+ bone marrow derived cells.

Aim: To test the ability of this method of hepatic parenchymal repopulation, theoretically applicable to clinical practice, to correct the metabolic disorder in a rat model of congenital hyperbilirubinaemia.

Methods and results: Analysis by confocal laser microscopy of fluorescence labelled cells and by immunohistochemistry for β2-microglubulin, 72 hours after intraportal delivery, showed engraftment of infused cells in liver parenchyma of rats with I/R, 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 I/R 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 hyperbilirubinaemic Gunn rats with deficient bilirubin conjugation after I/R damage resulted in 30% decrease in serum bilirubin, the appearance of bilirubin conjugates in bile, and the expression of normal UDP-glucuronyltransferase enzyme evaluated by polymerase chain reaction.

Conclusions: I/R 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 hyperbilirubinaemia in the Gunn rat.

  • ischaemia-reperfusion
  • liver regeneration
  • Crigler-Najjar disease
  • β2-microglubulin
  • green fluorescent protein
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Footnotes

  • Competing interests: None declared.

  • Abbreviations:
    β2m
    β2-microglobulin
    BMDC
    bone marrow derived cell
    DAPI
    4′,6-diamidino-2-phenylindole
    FAH
    fumarylacetoacetate hydrolase
    GFP
    green fluorescent protein
    I/R
    ischaemia/reperfusion
    JJ
    jaundiced Gunn

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