MESENCHYMAL STROMAL CELLS ENGINEERED TO PRODUCE IGF-I AMELIORATE LIVER FIBROSIS WITH INDUCTION OF HEPATIC REGENERATION IN MICE

ESTEBAN J. FIORE, JUAN M BAYO FINA, MARIANA G. GARCIA, MARIANA MALVICINI, RODRIGO LLOYD, FLAVIA PICCIONI, MANGLIO RIZZO, ESTANISLAO PEIXOTO, MARÍA BEATRIZ SOLA, CATALINA ATORRASAGASTI, LAURA ALANIZ, JESÚS PRIETO, JORGE B. AQUINO GUILLERMO MAZZOLINI

Congreso; International Society for Stem Cell Research Annual Meeting; 2014

Background and aims: Liver cirrhosis involves chronic damage and wound healing processes. Mesenchymal stromal cells (MSCs) were previously shownto support tissue repair. 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 an adenovirus codifying for IGF-I (AdIGF-I) or green fluorescence protein (AdGFP-MSCs). Fibrosis was induced in BALB/c mice by chronic administration of thioacetamide (TAA) 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. The effect of a single cellular dose treatment was compared with that of repeatedMSCs applications (3 doses) which were separated by 2 weeks in between. All animals were sacrificed at week 12. In vitroexperiments were aimed to evaluate the effect of AdGFP-MSCs or AdIGF-I-MSCs supernatants on CFSC-2G hepatic stellate cells and mouse hepatocyte primary cultures. Results: The application of AdIGF-I-MSCs resulted in a further amelioration of liver fibrosis when compared to AdGFP-MSCs,as shown by morphometric studies. Expressionlevels of pro-fibrogenic factors in liver samples and in hepatic stellate cells were consistent with AdIGF-I-MSCs exertinganti-fibrotic effects.In the liver, an induction in IGF-I and in hepatocyte growth factor (HGF) expression levels was observed at 1day and a downregulation inTGF-beta1 andalpha-SMA at 3 days after MSCs application, with higher levels found in samples from AdIGF-I-treated animals. In vitro studies also showed a reduction in HSCs activation and an upregulation in IGF-I and HGF mRNA expression in hepatocytesafter incubation with conditioned media from AdIGF-I-MSCs. Interestingly, an induction inPCNA mRNA and protein expression levels was found in the liver of AdIGF-I-treated animals at 1 day after transplantationsuggesting the involvement of regenerative mechanisms. Finally,multiple doses of Ad-IGF-I-MSCs further reduced collagen deposition when compared to a single dose treatment.