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Kim J.Y.,Korea University | Shaker M.R.,Korea University | Lee J.-H.,Korea University | Lee B.,Korea University | And 7 more authors.
Stem Cells | Year: 2016

Abstract: Neurogenesis occurs spontaneously in the subventricular zone (SVZ) of the lateral ventricle in adult rodent brain, but it has long been debated whether there is sufficient adult neurogenesis in human SVZ. Subcallosal zone (SCZ), a posterior continuum of SVZ closely associated with posterior regions of cortical white matter, has also been reported to contain adult neural stem cells (aNSCs) in both rodents and humans. However, little is known whether SCZ-derived aNSC (SCZ-aNSCs) can produce cortical neurons following brain injury. We found that SCZ-aNSCs exhibited limited neuronal differentiation potential in culture and after transplantation in mice. Neuroblasts derived from SCZ initially migrated toward injured cortex regions following brain injury, but later exhibited apoptosis. Overexpression of anti-apoptotic bcl-xL in the SCZ by retroviral infection rescued neuroblasts from cell death in the injured cortex, but neuronal maturation was still limited, resulting in atrophy. In combination with Bcl-xL, infusion of brain-derived neurotropic factor rescued atrophy, and importantly, a subset of such SCZ-aNSCs differentiated and attained morphological and physiological characteristics of mature, excitatory neurons. These results suggest that the combination of anti-apoptotic and neurotrophic factors might enable the use of aNSCs derived from the SCZ in cortical neurogenesis for neural replacement therapy. © 2016 AlphaMed Press.

Park H.-J.,Hanyang University | Park H.-J.,Hanyang Biomedical Research Institute | Kim D.-H.,Hanyang University | Kim D.-H.,Hanyang Biomedical Research Institute | And 14 more authors.
PLoS ONE | Year: 2014

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates lipid and glucose metabolism. Although studies of PPARγ ligands have demonstrated its regulatory functions in inflammation and adaptive immunity, its intrinsic role in T cells and autoimmunity has yet to be fully elucidated. Here we used CD4- PPARγKO mice to investigate PPARγ-deficient T cells, which were hyper-reactive to produce higher levels of cytokines and exhibited greater proliferation than wild type T cells with increased ERK and AKT phosphorylation. Diminished expression of IκBα, Sirt1, and Foxo1, which are inhibitors of NF-κB, was observed in PPARγ-deficient T cells that were prone to produce all the signature cytokines under Th1, Th2, Th17, and Th9 skewing condition. Interestingly, 1-year-old CD4- PPARγKO mice spontaneously developed moderate autoimmune phenotype by increased activated T cells, follicular helper T cells (T FH cells) and germinal center B cells with glomerular inflammation and enhanced autoantibody production. Sheep red blood cell immunization more induced TFH cells and germinal centers in CD4- PPARγKO mice and the T cells showed increased of Bcl-6 and IL-21 expression suggesting its regulatory role in germinal center reaction. Collectively, these results suggest that PPARγ has a regulatory role for TFH cells and germinal center reaction to prevent autoimmunity. © 2014 Park et al.

Choi J.-M.,Hanyang University | Choi J.-M.,Hanyang Biomedical Research Institute | Sohn J.-H.,Hanyang University | Sohn J.-H.,Hanyang Biomedical Research Institute | And 5 more authors.
Immunology Letters | Year: 2012

Nuclear factor of activated T cells (NFAT) is an important transcription factor for the production of interleukin (IL)-2 upon T-cell receptor (TcR) signaling. Therefore, inhibition of the NFAT-carcineurin pathway is an important target for inflammatory disease inhibition and graft rejection. A novel cell permeable peptide (CPP), Sim-2, has been identified from a human transcription factor, and Sim-2-CPP conjugated to . β-galactosidase or EGFP protein was efficiently delivered into cells . in vitro and . in vivo. A cell permeable form of the NFAT inhibitory peptide VIVIT (Sim-2-VIVIT) was synthesized and showed inhibitory effects on human CD4 or CD8 T-cell activation through NFAT transcriptional activity suppression and IL-2 inhibition. Intranasal administration of the Sim-2-VIVIT peptide in an ovalbumin (OVA)-induced murine asthma model alleviated peribronchial and perivascular infiltration of inflammatory cells in the lung and caused airway remodeling and airway hyper-responsiveness. These results suggest that cell permeable Sim-2-VIVIT peptide has clinical potential as an immunosuppressive agent for inflammatory diseases. © 2012 Elsevier B.V.

Lee J.E.,Hanyang University | Lee J.E.,Hanyang Biomedical Research Institute | Lim M.S.,Hanyang Biomedical Research Institute | Lim M.S.,Hanyang University | And 6 more authors.
NeuroToxicology | Year: 2014

Chlorpyrifos (CPF) is one of the most widely used organophosphate insecticides with several harmful effects, including neurotoxicity. Although many studies have addressed the neurotoxicity induced by CPF, most data on neurodevelopmental damage was obtained from animal models. We are the first group to use human neural precursor cells (hNPCs) derived from human embryonic stem cells (hESCs) as a developing neuron model to evaluate the mechanisms involved in CPF-induced neurotoxicity. CPF was cytotoxic to these cells in a concentration-dependent manner, as shown by decreased cell viability and increased lactate dehydrogenase release. Furthermore, CPF reduced the expression of AKT and ERK proteins which are involved in intracellular survival pathways. Exposure of hNPCs to CPF led to the production of reactive oxygen species (ROS), and the antioxidant N-acetyl-cystein (NAC) attenuated ROS production induced by CPF. In addition, CPF increased cytochrome c release into the cytosol and activated caspase-9 and -3, indicating that cell death induced by CPF was due to apoptosis in hNPCs. Consistent with these findings, CPF treatment reduced the level of Bcl-2 protein and increased the level of Bax protein. Especially, CPF increased the translocation of BAX into the mitochondria. CPF also induced nuclear accumulation of NF-κB and p53 proteins in a concentration-dependent manner, and their inhibitors attenuated CPF-induced cytotoxicity. In addition, an inhibitor of NF-κB nuclear translocation blocked the increase of p53 in CPF-treated hNPCs. These findings show that CPF induced hNPCs death in part through NF-κB activation via ROS generation, enabling the interaction of p53 with Bcl-2 and Bax and subsequent release of cytochrome c. Collectively, these results represent a unique molecular characterization of CPF-induced cytotoxicity in hNPCs. These data suggest that CPF may affect neurodevelopment in a manner similar to that of several known and suspected neurotoxicants. © 2014.

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