IIMT   25668
INSTITUTO DE INVESTIGACIONES EN MEDICINA TRASLACIONAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Homing and therapeutic potential of mesenchymal stromal cells as vehicles of antifibrotic genes in advanced liver fibrosis: key role of hepatic macrophages
Autor/es:
FIORE EJ; ATORRASAGASTI C; GARCIA MG; BAYO J; PICCIONI F; AQUINO J; MALVICINI M; PEIXOTO E; MAZZOLINI G
Lugar:
Mar del Plata
Reunión:
Congreso; LXI Reunión Cientifica anual de la Sociedad Argentina de Investigaciones clínicas; 2016
Resumen:
Hepatic macrophages (hMø) have apivotal role in liver fibrogenesis. esenchymal stromalcells (MSCs) are actively recruited to injury sites, showimmunomodulatory properties and can be a powerful toolas therapeutic gene carriers. We previously showed antifibroticeffects of in vivo application of SCs engineeredto exogenously express insulin growth factor like-I (IGFIMSCs). We aimed to characterize the main cytokinesproduced by the fibrotic liver involved in SCs recruitment.e also analyzed the influence exerted by SCs on hand if it could drive liver fibrosis resolution. etodologyExperimental liver fibrosis as induced in AL/c miceby 8 weeks administration of thioacetamide. For in vivotracking of administrated MSC we used Xenogen InVivoImaging System. Depletion of hMø was performed usingclodronate. Results: MSCs in vivo and in vitro migrationwas higher to cirrhotic livers in comparison with healthy livers.Also, MSCs displayed a high migration to CM derived from liver of cirrhotic patient or cirrhotic mice or a hepaticstellate cell line (LX2). Analysis of cytokines expressionby protein array of CM derived from patient and LX2 cellsshowed high levels of GRO, MCP-1 and IL-8. Incubation ofMSCs with antibody against IL-8/GRO receptors resultedin a 50% reduction of their migration capacity toward LX2C. h isolated from FSCs treated fibrotic liversshoed reduced expression levels of proinflammatoryand profibrogenic genes and an upregulation in proregenerativegenes vs. control conditions. Similarly,hMø from cirrhotic patients showed a similar shift afterincubation with CM from IGFI-MSCs. Factors secreted byMSCs preconditioned hMø reduced the activation statusof hepatic stellate cells. Finally, hMø depletion abrogatedthe therapeutic effect and the pro-regenerative stimuli ofIGF1 MSC therapy. Conclusions: Our data provide newearly mechanisms which are required for MSCs homing and FSCs liver fibrosis amelioration.