title: Human neonatal hepatocyte transplantation induces long-term rescue of unconjugated hyperbilirubinemia in the Gunn rat.
abstract: Crigler-Najjar type 1 disease is a rare inherited metabolic disease characterized by high levels of unconjugated bilirubin due to the complete absence of hepatic uridine diphosphoglucuronate-glucuronosyltransferase activity. Hepatocyte transplantation (HT) has been proposed as an alternative treatment for Crigler-Najjar syndrome, but it is still limited by the quality and the low engraftment and repopulation ability of the cells used. Because of their attachment capability and expression of adhesion molecules as well as the higher proportion of hepatic progenitor cells, neonatal hepatocytes may have an advantage over adult cells. Adult or neonatal hepatocytes were transplanted into Gunn rats, a model for Crigler-Najjar disease. Engraftment and repopulation were studied and compared by immunofluorescence (IF). Additionally, the serum bilirubin levels, the presence of bilirubin conjugates in rat serum, and the expression of uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) in rat liver samples were also analyzed. Here we show that neonatal HT results in long-term correction in Gunn rats. In comparison with adult cells, neonatal cells showed better engraftment and repopulation capability 3 days and 6 months after transplantation, respectively. Bilirubinemia decreased in the transplanted animals during the whole experimental follow-up (6 months). Bilirubin conjugates were also present in the serum of the transplanted animals. Western blots and IF confirmed the presence and expression of UGT1A1 in the liver. This work is the first to demonstrate the advantage of using neonatal hepatocytes for the treatment of Crigler-Najjar in vivo.
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Tolosa
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: López
authors.affiliation: Unidad de Cirugía Hepatobiliopancreática y Transplante Hepático, Hospital La Fe, Valencia, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Pareja
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Fondo de Investigaciones Sanitarias, Barcelona, Spain.|Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Donato
authors.affiliation: Service de Biologie, Groupe Hospitalier Saint Joseph, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Myara
authors.affiliation: INSERM Unités Mixtes de Recherche en Santé 1064, Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France.
authors.forename: Tuan Huy
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Fondo de Investigaciones Sanitarias, Barcelona, Spain.|Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: José Vicente
authors.initials: JV
authors.lastname: Castell
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Fondo de Investigaciones Sanitarias, Barcelona, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Gómez-Lechón
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001663:Bilirubin / Q000097:blood; D049109:Cell Proliferation; D003414:Crigler-Najjar Syndrome / Q000628:therapy*; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000637:transplantation*; D006801:Humans; D007231:Infant, Newborn; D008099:Liver / Q000378:metabolism; D008115:Liver Regeneration; D008297:Male; D008875:Middle Aged; D011433:Propranolol; D011911:Rats, Gunn; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D011433:Propranolol; D000099148:UGT1A1 Enzyme