title: Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells.
abstract: OBJECTIVE
  Cell therapy has been used to attenuate liver injury. Here we evaluated whether genetic engineering of either bone marrow-derived mononuclear cells (MNC) or endothelial progenitor cells (EPC) many enhance their hepatoprotective properties.
  
  
  METHODS
  Mice with ConA-induced hepatitis or with lethal fulminant hepatitis resulting from administration of an adenovirus encoding CD40L (AdCD40L) received an intra-splenic injection of saline or 2 × 10(6) unmodified MNC or EPC or the same cells transduced ex vivo with an adenovirus expressing luciferase (MNCLUC and EPCLUC) or encoding the hepatoprotective cytokine cardiotrophin-1 (CT-1) (MNCCT-1 and EPCCT-1). We analyzed the extent of liver damage, the intensity of inflammatory reaction, and animal survival.
  
  
  RESULTS
  Luciferase immunohistochemistry showed that after injection into the spleen, the engineered cells migrated efficiently to the damaged liver. In mice with ConA hepatitis EPCCT-1, but not other forms of cell therapy, significantly decreased serum transaminases and induced more intense histological improvement than other treatments. This superior therapeutic effect was associated with upregulation of cytoprotective molecules including IGF-I and EGF, lower expression of proinflammatory cytokines, IL-1b and TNFα, and decreased granzyme B levels. In AdCD40L-induced lethal fulminant hepatitis, EPCCT-1 also exceeded other cell therapies in attenuating the expression of proinflammatory mediators and hepatic injury enabling 35.7% survival while mortality was 100% in the other treatment groups.
  
  
  CONCLUSIONS
  Genetic engineering of EPC to overexpress CT-1 enhances the hepatoprotective properties of EPC and constitutes a therapy that deserves consideration for acute liver failure.
authors.affiliation: Center for Applied Medical Research (CIMA), Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Fernandez-Ruiz
authors.forename: Milosz
authors.initials: M
authors.lastname: Kawa
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: Maria
authors.initials: M
authors.lastname: Iñiguez
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martinez-Ansó
authors.forename: Mercedes
authors.initials: M
authors.lastname: Iñarrairaegui
authors.forename: Ignacio
authors.initials: I
authors.lastname: Herrero
authors.forename: Bruno
authors.initials: B
authors.lastname: Sangro
authors.forename: Delia
authors.initials: D
authors.lastname: D'Avola
authors.forename: Jorge
authors.initials: J
authors.lastname: Quiroga
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000628:therapy; D003208:Concanavalin A / Q000633:toxicity; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology*; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D017114:Liver Failure, Acute / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000633:toxicity; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D010641:Phenotype; D000074058:Solute Carrier Family 22 Member 5; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D015996:Survival Rate; D019076:Transgenes / Q000235:genetics
chemical_list: D008934:Mitogens; D027701:Organic Cation Transport Proteins; C492019:Slc22a5 protein, mouse; D000074058:Solute Carrier Family 22 Member 5; D003208:Concanavalin A