title: Improvement of hepatocyte transplantation efficiency in the mdr2-/- mouse model by glyceryl trinitrate.
abstract: BACKGROUND
  Hepatocyte transplantation could be an alternative to liver transplantation for the treatment of metabolic diseases. However, rodent models have shown that engraftment of transplanted cells in the liver is low and requires deposition of cells in hepatic sinusoids. Splanchnic vasodilatators improved hepatocyte engraftment in a rat model. Therefore, we investigated the effect of glyceryl trinitrate (GTN) on the efficacy of cell engraftment and on liver repopulation in the mdr2-knockout mouse, a model for progressive familial intrahepatic cholestasis type 3.
  
  
  METHODS
  Congenic normal mdr2 (+/+) hepatocytes were isolated by two-step collagenase perfusion and transplanted into mdr2(-/-) mice livers through the portal vein in the presence or absence of GTN. Liver repopulation was assessed by immunohistochemistry, and transplanted hepatocyte function was assessed at different times after transplantation by measurement of biliary lipid secretion and quantification of fibrosis.
  
  
  RESULTS
  The number of engrafted cells in GTN-treated mice was significantly higher than that in control mice, and transplanted hepatocytes were found in a greater number of distal sinusoids. Levels of phospholipid secretion were significantly higher than those in the control group 3 months after hepatocyte transplantation (18.3 ± 2.3 vs. 5.2 ± 3.9 nmol/min/100 g, P < 0.0001), and the ratio of phospholipids to bile salt was greater (6.8 ± 1.3 vs. 3.2 ± 1.6, P = 0.03). The percentage area of liver fibrosis was also significantly reduced in GTN-treated mice (5.7% ± 2.3% vs. 12.4% ± 2.9%, P = 0.016).
  
  
  CONCLUSIONS
  The use of GTN improves hepatocyte engraftment and correction of metabolic disease in mdr2 (-/-) mice. This approach might be beneficial in hepatocyte transplantation for the treatment of patients with liver diseases.
authors.affiliation: 1 INSERM U 972, Paul-Brousse Hospital, Villejuif, France. 2 Paris-Sud University, Orsay, France. 3 Department of Minimally Invasive Surgery, Antoine-Béclère Hospital, AP-HP, Clamart, France. 4 Department of Pediatric Surgery, Bicêtre Hospital, AP-HP, Kremlin-Bicêtre, France. 5 Department of Biochemistry, Bicêtre Hospital, AP-HP, Kremlin-Bicêtre, France.
authors.forename: Lyes
authors.initials: L
authors.lastname: Boudechiche
authors.forename: Hadrien
authors.initials: H
authors.lastname: Tranchart
authors.forename: Sophie
authors.initials: S
authors.lastname: Branchereau
authors.forename: Anne
authors.initials: A
authors.lastname: Davit-Spraul
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Laïnas
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Groyer-Picard
authors.forename: Anne
authors.initials: A
authors.lastname: Weber
authors.forename: Michelle
authors.initials: M
authors.lastname: Hadchouel
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Dagher
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002780:Cholestasis, Intrahepatic / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D018345:Mice, Knockout; D005996:Nitroglycerin / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D013997:Time Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D005996:Nitroglycerin; D010743:Phospholipids; D000097202:ATP-Binding Cassette Sub-Family B Member 4