Homing and therapeutic potential of mesenchymal stromal cells as vehicles of antifibrotic genes in advanced liver fibrosis: key role of hepatic macrophages

FIORE EJ; BAYO J; MALVICINI M; ATORRASAGASTI C; PICCIONI F; PEIXOTO E; GARCIA MG; AQUINO J; MAZZOLINI G

Mar del Plata

Congreso; LXI Reunión Cientifica anual de la Sociedad Argentina de Investigaciones clínicas; 2016

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 h􀀯􀃓and if it could drive liver fibrosis resolution. 􀀯etodology􀀜Experimental 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 􀀫􀀩F􀀫􀀏􀀯SCs treated fibrotic liverssho􀁙ed reduced expression levels of pro􀀏inflammatoryand pro􀀏fibrogenic genes and an up􀀏regulation 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.