title: Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice.
abstract: Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells (MSCs) are multipotent adult progenitor cells that are used as vehicles of therapeutic genes. Insulin growth factor like-I (IGF-I) was shown to counteract liver fibrosis. We aimed at analyzing the effect of applying IGF-I overexpressing mouse bone marrow-derived MSCs on hepatic fibrosis. Fibrosis was induced by chronic thioacetamide application or bile duct ligation. MSCs engineered to produce green fluorescent protein (GFP) (AdGFP-MSCs) or IGF-I (AdIGF-I-MSCs) were applied systemically, and changes in collagen deposition and in the expression of key pro-fibrogenic and pro-regenerative genes/proteins were assessed. In addition, immunogenicity of transduced cells was analyzed. Liver fibrosis was further ameliorated after a single-dose application of AdIGF-I-MSCs when compared with AdGFP-MSCs and/or recombinant IGF-I treatments. Interestingly, an early and transitory upregulation in IGF-I and hepatocyte growth factor (HGF) mRNA expression was found in the liver of MSC-treated animals, which was more pronounced in AdIGF-I-MSCs condition. A reduction in hepatic stellate cell activation status was found after incubation with MSCs conditioned media. In addition, the AdIGF-I-MSCs cell-free supernatant induced the expression of IGF-I and HGF in primary cultured hepatocytes. From day 1 after transplantation, the proliferation marker proliferating cell nuclear antigen was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs were in vivo traced till day 14 after injection. In addition, multiple doses of Ad-IGF-I-MSCs likely suppressed antiviral immune response and it further reduced collagen deposition. Our results uncover early events that are likely involved in the anti-fibrogenic effect of genetically modified MSCs and overall would support the use of AdIGF-I-MSCs in treatment of liver fibrosis.
authors.affiliation: 1 Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral , Buenos Aires, Argentina .
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Fiore
authors.forename: Juan M
authors.initials: JM
authors.lastname: Bayo
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Garcia
authors.forename: Mariana
authors.initials: M
authors.lastname: Malvicini
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Lloyd
authors.forename: Flavia
authors.initials: F
authors.lastname: Piccioni
authors.forename: Manglio
authors.initials: M
authors.lastname: Rizzo
authors.forename: Estanislao
authors.initials: E
authors.lastname: Peixoto
authors.forename: M Beatriz
authors.initials: MB
authors.lastname: Sola
authors.forename: Catalina
authors.initials: C
authors.lastname: Atorrasagasti
authors.forename: Laura
authors.initials: L
authors.lastname: Alaniz
authors.forename: María A
authors.initials: MA
authors.lastname: Camilletti
authors.forename: Mónica
authors.initials: M
authors.lastname: Enguita
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Aquino
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mazzolini
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D005355:Fibrosis / Q000628:therapy; D015316:Genetic Therapy; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000628:therapy*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D007334:Insulin-Like Growth Factor I