P1 - Enfermedades humanas

Mesenchymal stem cell–derived extracellular vesicles loaded with IGF-I as a therapeutic strategy for posthepatectomy liver regeneration

Casadei, Mailín ¹ - Cantero, María José ¹ - Bueloni, Bárbara ¹ - Huamán Ormeño, Fátima ¹ - Lameroli, Lucía - Atorrasagasti, Catalina ¹ - Bayo, Juan ¹ - Mazzolini, Guillermo ¹ - Fiore, Esteban ¹

1) Programa de Hepatología Experimental y Terapia Génica, Instituto de Investigaciones de Medicina Traslacional, Universidad Austral – CONICET, Pilar, Argentina
Contacto: mcasadei@austral.edu.ar

Background and Aims: Liver transplantation is currently the only curative treatment for end-stage liver diseases. Impaired regeneration after liver resection may cause liver failure. Because extracellular vesicles (EV) derived from mesenchymal stem cells largely reproduce their immunomodulatory, cytoprotective, and pro-regenerative effect, they are proposed as an alternative to cell therapy. Furthermore, EV are also emerging as a strategy to deliver therapeutic genes. We have recently demonstrated in experimental models of liver injury that the therapeutic effect of MSC from the umbilical cord (human umbilical cord perivascular cells, HUCPVC), genetically modified to express the hepatoprotective and pro-regenerative factor IGF-I (insulin-like growth factor I), is mediated by EV. Furthermore, these EV carry IGF-I and enhance its therapeutic effect. The aim was to evaluate the effect on liver regeneration of EV carrying IGF-I on partial hepatectomy (PH) model in mice.
Method: EV were isolated by ion exchange chromatography from supernatants of HUCPVC infected with adenoviruses codifying for green fluorescent protein (GFP-EV) or IGF-I (IGF-I-EV). Nanoparticle tracking analysis (NTA) was used to determine EV concentration and size distribution. PH of 66% of liver mass were performed on adult C57BL6 mice. After 1 hour of PH, vehicle- GFP-EV- or IGF-I -EV were administered by tail vein (1 dose, 50 microgram/mice) and 3 days later animals were euthanized to liver sample collect. Liver index was calculated as ratio of liver/body weight and liver regeneration rate as % of recovered liver mass. qPCR and histological analysis were performed on liver sample.
Results: In vivo treatment with IGF-I-EV led to a higher LI and LRR compared to controls groups. An increase in PCNA+ cells following IGF-I-EV administration indicated enhanced liver regeneration. Moreover, IGF-I-EV treatment upregulated markers associated with hepatocyte proliferation. In contrast, the treatment with IGF-I-EV reduces the expression of pro-inflammatory genes such as IL-1, TNF and iNOS.

Conclusion: Our findings provide experimental evidence supporting IGF-I-EV as a promising therapeutic
agent for enhancing liver regeneration following surgical injury.

Palabras clave: INSULIN-LIKE GROWTH FACTOR I, PARTIAL HEPATECTOMY, LIVER REGENERATION