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

FIORE E; BAYO J; GARCIA MG; MALVICINI M; LLOYD R; PICCIONI F; RIZZO M; PEIXOTO E; ATORRASAGASTI C; ALANIZ L; AQUINO JB; MAZZOLINI G

Londres

Congreso; 49º Congreso Internacional de Higado de la Sociedad Europea para el; 2014

Abstract Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells (MSCs) are multipotent adult progenitor cells being 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 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 single dose application of AdIGF-I-MSCs when compared to AdGFP-MSCs and/or recombinant IGF-I treatments. Interestingly, an early and transitory upregulation in IGF-I and 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 cells 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 PCNA was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs were in vivo traced up to 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 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.