Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells (MSCs) are multipotent adult progenitor cells that are used as vehicles of therapeutic genes.
Insulin growth factor like-I (
IGF-I) was shown to counteract
liver fibrosis. We aimed at analyzing the effect of applying
IGF-I overexpressing mouse bone marrow-derived MSCs on hepatic
fibrosis.
Fibrosis was induced by chronic
thioacetamide application or bile duct
ligation. MSCs engineered to produce
green fluorescent protein (GFP) (AdGFP-MSCs) or
IGF-I (AdIGF-I-MSCs) were applied systemically, and changes in
collagen deposition and in the expression of key pro-fibrogenic and pro-regenerative genes/
proteins were assessed. In addition, immunogenicity of transduced cells was analyzed.
Liver fibrosis was further ameliorated after a single-dose application of AdIGF-I-MSCs when compared with AdGFP-MSCs and/or recombinant
IGF-I treatments. Interestingly, an early and transitory upregulation in
IGF-I and
hepatocyte growth factor (HGF)
mRNA expression was found in the liver of MSC-treated animals, which was more pronounced in AdIGF-I-MSCs condition. A reduction in hepatic stellate cell activation status was found after incubation with MSCs
conditioned media. In addition, the AdIGF-I-MSCs cell-free supernatant induced the expression of
IGF-I and HGF in primary cultured hepatocytes. From day 1 after
transplantation, the proliferation marker
proliferating cell nuclear antigen was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs were in vivo traced till day 14 after injection. In addition, multiple doses of Ad-
IGF-I-MSCs likely suppressed
antiviral immune response and it further reduced
collagen deposition. Our results uncover early events that are likely involved in the anti-fibrogenic effect of genetically modified MSCs and overall would support the use of AdIGF-I-MSCs in treatment of
liver fibrosis.