RESUMO
Neurogenesis decline in hippocampal dentate gyrus (DG) participates in stress-induced depressive-like behaviors, but the underlying mechanism remains poorly understood. Here, we observed low-expression of NOD-like receptor family pyrin domain containing 6 (NLRP6) in hippocampus of stress-stimulated mice, being consistent with high corticosterone level. NLRP6 was found to be abundantly expressed in neural stem cells (NSCs) of DG. Both Nlrp6 knockout (Nlrp6-/-) and NSC-conditional Nlrp6 knockout (Nlrp6CKO) mice were susceptible to stress, being more likely to develop depressive-like behaviors. Interestingly, NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up. Nlrp6 deficiency promoted esophageal cancer-related gene 4 (ECRG4) expression and caused mitochondrial dysfunction. Corticosterone as a stress factor significantly down-regulated NLRP6 expression, damaged mitochondrial function and suppressed cell proliferation in NSCs, which were blocked by Nlrp6 overexpression. ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders. Pioglitazone, a well-known clinical drug, up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction. In conclusion, this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs, and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.
RESUMO
BACKGROUND:In vitro studies have demonstrated that basic fibroblast growth factor (bFGF) promote the differentiation of bone marrow mesenchymal stem cells (BMSCs) into cardiomyocyte-like cells. However, it is unclear whether coronary venous retroperfusion of bFGF stimulates BMSCs differentiation in vivo. OBJECTIVE:To evaluate the effects of coronary venous retroperfusion of bFGF on BMSCs differentiation in vivo. METHODS:BMSCs from 12 dogs were isolated by density gradient centrifugation and expanded in vitro. These cells were transfected by enhanced green fluorescence protein (EGFP) lentiviral vector and the transfection efficiency was analyzed. Acute myocardial infarction was induced by ligation of left anterior descending coronary artery. After 1 week, 10 survival animals were randomized to BMSCs group (n=5) and bFGF+BMSCs group (n=5). bFGF-and EGFP-positive BMSCs were reversely infused via coronary vein using over-the-wire bal oon catheter. One week after infusion, the number of EGFP-positive cells co-staining factor VIII and troponin I was compared between the two groups by immunofluorescence method. RESULTS AND CONCLUSION:BMSCs were successful y transfected by EGFP and the transfection efficiency was 85%. Immunofluorescence showed that EGFP-positive BMSCs were observed in 23.5%of slides. There were more EGFP-positive cells co-staining VIII and troponin I in the bFGF+BMSCs group than in the BMSCs group (P<0.05). Thus, the coronary venous retroperfusion of bFGF enhances the differentiation of BMSCs into vascular endothelial cells and cardiomyocytes. Combined delivery of bFGF and BMSCs can exert a synergistic effect to promote cardiac repair.
RESUMO
10.3969/j.issn.2095-4344.2013.24.015