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

ESTEBAN FIORE; JUAN BAYO; MARIANA GARCIA; MARIANA MALVICINI; RODRIGO LLOYD; FLAVIA PICCIONI; MIGUEL RIZZO; ESTANISLAO PEIXOTO; BEATRÍZ SOLÁ; CATALINA ATORRASAGASTI; LAURA ALANIZ; JESÚS PRIETO; JORGE AQUINO; GUILLERMO MAZZOLINI

Londres

Congreso; European Association for the Study of theLiver; 2014

Background and Aims: Mesenchymal stromal cells (MSCs) showhigh capacity for being recruited to injured areas. Insulin GrowthFactor like-I (IGF-I) is known to counteract fibrosis and to inducehepatocytes proliferation and survival. We aimed to evaluatethe effects of applying MSCs engineered to produce IGF-I in anexperimental in vivo model of advanced liver fibrosis.Methods: Bone marrow MSCs from BALB/c mice were infected withadenoviruses codifying for IGF-I (AdIGF-I) or green fluorescenceprotein (AdGFP-MSCs). Fibrosis was induced in BALB/c mice bychronic administration of thioacetamide during 8 weeks. Onweek 6, AdIGF-I-MSCs, AdGFP-MSCs or saline were intravenouslyadministered in fibrotic animals which were sacrificed at 1, 3 or 14days after treatment. In vitro studies were performed using the ratCFSC-2G hepatic stellate cell line and hepatocyte primary cultures.Results: The application of AdIGF-I-MSCs resulted in a furtheramelioration of liver fibrosis when compared to AdGFP-MSCscondition. An upregulation in IGF-I and hepatocyte growth factor(HGF) mRNA expression in the liver was found at 1 day after MSCsapplication. A reduction in HSCs activation and an induction inthe IGF-I and HGF mRNA expression levels by cultured hepatocyteswere found when those cells were incubated with conditionedmedia from AdIGF-I-MSCs. Interestingly, from 1 day after treatmentan induction in PCNA mRNA and protein expression levels wasfound in AdIGF-I-treated animals.Conclusions: Our data support the use of AdIGF-I-MSCs astherapeutic tools in treatment of liver fibrosis, and uncover earlyevents likely involved in their anti-fibrogenic effect.