Insulin-Like Growth Factor I (IGF-I) Expressed from an AAV1 Vector Leads to a Complete Reversion of Liver Cirrhosis in Rats | Zendy

Luciano Sobrevals | Zendy; Mónica Enguita | Zendy; Jorge Quiroga | Zendy; Jesús Prìeto | Zendy; Puri Fortes | Zendy

Open Access

Insulin-Like Growth Factor I (IGF-I) Expressed from an AAV1 Vector Leads to a Complete Reversion of Liver Cirrhosis in Rats

Author(s) -

Luciano Sobrevals,

Mónica Enguita,

Jorge Quiroga,

Jesús Prìeto,

Puri Fortes

Publication year - 2016

Publication title -

plos one

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 0.99

H-Index - 332

ISSN - 1932-6203

DOI - 10.1371/journal.pone.0162955

Subject(s) - ctgf , downregulation and upregulation , endocrinology , cirrhosis , hepatic stellate cell , growth factor , medicine , vascular endothelial growth factor , insulin like growth factor , biology , gdf15 , connective tissue , receptor , pathology , biochemistry , vegf receptors , gene

IGF-I modulates liver tissue homeostasis. It is produced by hepatocytes and signals within the liver through IGF-I receptor expressed on hepatic stellate cells (HSCs). Liver cirrhosis is characterized by marked IGF-I deficiency. Here we compared the effect of two different gene therapy vectors encoding IGF-I as a potential treatment for cirrhotic patients. Rats with carbon tetrachloride-induced liver cirrhosis were treated with controls or with adeno-associated virus 1 (AAV) or simian virus 40 (SV40) vectors expressing IGF-I (AAVIGF-I or SVIGF-I) and molecular and histological studies were performed at 4 days, 8 weeks and 16 weeks. Increased levels of IGF-I were observed in the liver as soon as 4 days after vector administration. Control cirrhotic rats showed increased hepatic expression of pro-inflammatory and pro-fibrogenic factors including transforming growth factor beta (TGFβ), tumor necrosis factor-alpha (TNFα), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF) together with upregulation of α-smooth muscle actin (αSMA), a marker of HSC activation. In IGF-I-treated rats the levels of all these molecules were similar to those of healthy controls by week 8 post-therapy. Of note, the decline of TGFβ, CTGF, VEGF and αSMA expression was more rapid in AAVIGF-I treated animals reaching statistical significance by day 4 post-therapy. IGF-I-treated rats showed similar improvement of liver function tests in parallel with upregulation of hepatocyte nuclear factor 4α (HNF4α), a factor that promotes hepatocellular differentiation. A significant decrease of liver fibrosis, accompanied by upregulation of the hepatoprotective and anti-fibrogenic hepatocyte growth factor (HGF), occurred in all IGF-I-treated rats but complete reversal of liver cirrhosis took place only in AAVIGF-I group. Therefore, AAVIGF-I reverts liver cirrhosis in rats, a capability which deserves clinical testing.

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