MESENCHYMAL STROMAL CELLS ENGINEERED TO PRODUCE IGF-I AMELIORATE LIVER FIBROSIS IN MICE

E.J. FIORE, J.M. BAYO FINA, M. GARCÍA, M. MALVICINI, R. LLOYD, F. PICCIONI, M.M. RIZZO, E. PEIXOTO, C. ATORRASAGASTI L. ALANIZ J.B. AQUINO G.D. MAZZOLINI

Congreso; The International Liver Congress; 2014

EASL

Background and Aims: Mesenchymal stromal cells (MSCs) show high capacity for being recruited to injured areas. Insulin Growth Factor like-I (IGF-I) is known to counteract fibrosis and to induce hepatocytes proliferation and survival. We aimed to evaluate the effects of applying MSCs engineered to produce IGF-I in an experimental in vivo model of advanced liver fibrosis. Methods: Bone marrow MSCs from BALB/c mice were infected with adenoviruses codifying for IGF-I (AdIGF-I) or green fluorescence protein (AdGFP-MSCs). Fibrosis was induced in BALB/c mice by chronic administration of thioacetamide during 8 weeks. On week 6, AdIGF-I-MSCs, AdGFP-MSCs or saline were intravenously administered in fibrotic animals which were sacrificed at 1, 3 or 14 days after treatment. In vitro studies were performed using the rat CFSC-2G hepatic stellate cell line and hepatocyte primary cultures. Results: The application of AdIGF-I-MSCs resulted in a further amelioration of liver fibrosis when compared to AdGFP-MSCs condition. An upregulation in IGF-I and hepatocyte growth factor (HGF) mRNA expression in the liver was found at 1 day after MSCs application. A reduction in HSCs activation and an induction in the IGF-I and HGF mRNA expression levels by cultured hepatocytes were found when those cells were incubated with conditioned media from AdIGF-I-MSCs. Interestingly, from 1 day after treatment an induction in PCNA mRNA and protein expression levels was found in AdIGF-I-treated animals. Conclusions: Our data support the use of AdIGF-I-MSCs as therapeutic tools in treatment of liver fibrosis, and uncover early events likely involved in their anti-fibrogenic effect.