Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice

FIORE, E; BAYO J; GARCIA M; MALVICINI M; LLOYD, R; PICCIONI, F; RIZZO, M; PEIXOTO, E; SOLA MB; ATORRASAGASTI C; ALANIZ L; CAMILLETTI MA; ENGUITA, M; PRIETO, J; AQUINO J; MAZZOLINI G

STEM CELLS AND DEVELOPMENT

MARY ANN LIEBERT INC

Lugar: New York; Año: 2015

1547-3287

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 factorlike-I (IGF-I) was shown to counteract liver fibrosis. We aimed at analyzing the effect of applying IGF-Ioverexpressing mouse bone marrow-derived MSCs on hepatic fibrosis. Fibrosis was induced by chronicthioacetamide 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 andin the expression of key pro-fibrogenic and pro-regenerative genes/proteins were assessed. In addition, immunogenicityof transduced cells was analyzed. Liver fibrosis was further ameliorated after a single-doseapplication 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 expressionwas found in the liver of MSC-treated animals, which was more pronounced in AdIGF-I-MSCscondition. A reduction in hepatic stellate cell activation status was found after incubation with MSCs conditionedmedia. In addition, the AdIGF-I-MSCs cell-free supernatant induced the expression of IGF-I and HGF inprimary cultured hepatocytes. From day 1 after transplantation, the proliferation marker proliferating cellnuclear antigen was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs werein vivo traced till day 14 after injection. In addition, multiple doses of Ad-IGF-I-MSCs likely suppressedantiviral immune response and it further reduced collagen deposition. Our results uncover early events that arelikely involved in the anti-fibrogenic effect of genetically modified MSCs and overall would support the use ofAdIGF-I-MSCs in treatment of liver fibrosis.