Involvement of hepatic macrophages in the antifibrotic effect of IGF-I overexpressing mesenchymal stromal cells

BAYO J; SIERRA R; GARCÍA MG; MALVICINI M; FIORE EJ; ATORRASAGASTI C; PEIXOTO E; GÓMEZ BUSTILLO S; RODRIGUEZ M; MAZZOLINI G; AQUINO JB

Stem cell research & therapy

BioMed Central

Lugar: Londres; Año: 2016 vol. 7 p. 172 - 172

1757-6512

Background: Cirrhosis is a major health problem worldwide and new therapeutic strategies are urgently needed. Hepatic macrophages (hMø) have a pivotal role in liver fibrosis, being able to act in both its promotion and its resolution. It is well known that mesenchymal stromal cells (MSCs) can modulate the immune/inflammatory cells. However, the effects of MSCs over immune cells, particularly on hMø, in the context of liver fibrosis remain unclear. We previously described evidences of anti-fibrotic effects of in vivo applying MSCs, which were enhanced by forced over-expression of insulin growth factor like-I (AdIGF I MSCs). The aim of this work was to analyze the effect of MSCs on hMø behavior in the context of liver fibrosis resolution. Methods: Fibrosis was induced in BALB/c mice by chronic administration of thioacetamide (TAA) during 8 weeks. In vivo gene expression analyses, in vitro experiments using hMø isolated from the nonparenchymal liver cells fraction and in vivo experiments with depletion of Mø were performed. Results: One day after treatment, hMø isolated from fibrotic livers of MSCs-treated animals showed reduced pro-inflammatory and pro-fibrogenic gene expression profiles. These shifts were more pronounced in AdIGF-I-MSCs condition. Noteworthy, this group showed a significant upregulation in the expression of arginase-1 and a higher downregulation of iNOS expression thus suggesting decreased levels of oxidative stress. Moreover, a significant upregulation in IGF-I and HGF expression levels were observed in hMø from AdIGF-I-MSCs treated animals suggesting a restorative phenotype in these cells. Factors secreted by hMø, which were preconditioned with MSCs supernatant, caused a reduction in the expression levels of hepatic stellate cells pro-fibrogenic and activation markers. Interestingly, hMø depletion significantly abrogated the therapeutic effect achieved with AdIGF I MSCs therapy. Expression profile analyses for cell cycle markers were performed on fibrotic liver samples after treatment with AdIGF I MSCs and showed a significant regulation in genes related to DNA synthesis and repair quality control, cell cycle progression and DNA damage/cellular stress compatible with early induction of pro-regenerative and hepatoprotective mechanisms. Moreover, depletion of hMø abrogated such effects on the expression of the most highly regulated genes. Altogether, our results indicate that AdIGF-I-MSCs is able to induce a pro-fibrotic to resolutive phenotype shift on hepatic macrophages, which is key early event driving liver fibrosis amelioration.