INVESTIGADORES
FIORE Esteban Juan
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:
ESTEBAN FIORE; JUAN BAYO; MARIANA MALVICINI; ESTANISLAO PEIXOTO; CATALINA ATORRASAGASTI; ALEJANDRINA REAL; MARCELORODRIGUEZ; SOFÍA GOMEZ BUSTILLO; MARIANA GARCIA; JORGE AQUINO; GUILLERMO MAZZOLINI
Lugar:
Mar del Plata
Reunión:
Congreso; LXI Reunión científica anual de la Sociedad Argentina de Investigación Clínica; 2016
Institución organizadora:
Sociedad Argentina de Investigación Clínica (SAIC) y la Sociedad Argentina de Fisiología (SAFIS)
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 engineeredto 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 hMÓ and if it could drive liver fibrosis resolution. Metodology Experimental liver fibrosis Yas induced in BALb/c mice by 8 weeks administration of thioacetamide. For in vivo tracking of administrated MSC we used Xenogen InVivo Imaging 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. hMÓ isolated from IGF MSC treated fibrotic livers showed reduced expression levels of proinflammatory and profibrogenic genes and an upregulation in proregenerativegenes 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 liver fibrosis amelioration.