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

FIORE E; BAYO J; GARCÍA 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 Hígado de la Sociedad Europea para el estudio del hígado.; 2014

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.