INVESTIGADORES
GARCIA Mariana Gabriela
congresos y reuniones científicas
Título:
Homing and therapeutci potential of mesenchymal stromal cells as vehicles of antifibrotic genes in advanced liver fibrosis: key role of hepatic macrophages.
Autor/es:
FIORE EJ; BAYO J; MALVICINI M; PEIXOTO E; ATORRASAGASTI C; REAL A; RODRÍGUEZ M; GÓMEZ BUSTILLO S; GARCIA MG; AQUINO J; MAZZOLINI G
Reunión:
Congreso; Reunión anual conjunta de SAIC, SAI, SAFE, NANOMEDAR Y AACYTAL.; 2016
Resumen:
Background: Hepatic macrophages (hMø) have a pivotal role in liver fibrogenesis. Mesenchymal stromal cells (MSCs) are actively recruited to injury sites, show immunomodulatory properties and can be a powerful tool as therapeutic gene carriers. We previously showed antifibrotic effects of in vivo application of MSCs engineered to exogenously express insulin growth factor like-I (IGFI MSCs). We aimed to characterize the main cytokines produced by the fibrotic liver involved in MSCs recruitment. We also analyzed the influence exerted by MSCs on hMø and if it could drive liver fibrosis resolution. Metodology: Experimental liver fibrosis was induced in BALB/c mice by 8 weeks administration of thioacetamide. For in vivo tracking of administrated MSC we used Xenogen InVivoImaging System. Depletion of hMø was performed using clodronate. Results: MSCs in vivo and in vitro migration was 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 hepatic stellate cell line (LX2). Analysis of cytokines expression by protein array of CM derived from patient and LX2 cells showed high levels of GRO, MCP-1 and IL-8. Incubation of MSCs with antibody against IL-8/GRO receptors resulted in a 50% reduction of their migration capacity toward LX2 CM. hMø isolated from IGFI-MSCs treated fibrotic livers showed reduced expression levels of pro-inflammatory and pro-fibrogenic genes and an up-regulation in proregenerative genes vs. control conditions. Similarly, hMø from cirrhotic patients showed a similar shift after incubation with CM from IGFI-MSCs. Factors secreted by MSCs preconditioned hMø reduced the activation status of hepatic stellate cells. Finally, hMø depletion abrogated the therapeutic effect and the pro-regenerative stimuli of IGF1 MSC therapy. Conclusions: Our data provide new early mechanisms which are required for MSCs homing and IGFI-MSCs liver fibrosis amelioration.