New insights into progesterone actions on prolactin secretion and prolactinoma development.

Progesterone (P4) has controversial physiological effects on the regulation of the lactotroph population. While some studies have shown a negative role for P4 in prolactin secretion and lactotroph proliferation, antagonizing estradiol effects, others demonstrated a proliferative role of P4 at the pituitary level. Usually, progesterone actions in the pituitary gland were studied through their classical, genomic pathways triggered by nuclear progesterone receptors (nPRs). However, in 2003, the scene became more complex with the discovery of another group of progesterone receptors involved in rapid, non-genomic P4 effects: the membrane progesterone receptors (mPRs), which are members of the progesterone and adipoQ receptor (PAQR) family. This review examines the historical background and current data on the study of progesterone actions on PRL secretion providing new evidence of P4 effects at the hypothalamic and at the pituitary level through non-classic P4-receptors. In addition, we explore the role of progesterone in the development of experimental prolactinomas, a controversial topic in the literature.

Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice.

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.