Neural stem cells (NSCs) are multipotential progeniotr cells, which can generate neurons, astrocytes, and oligodendrocytes, the three major cell types in the central nervous system. They also have the self-renewal activity and can be expanded in an undifferentiated state in vitro. Due to their capability of multipotency and chemotaxis for lesion site, there has been increasing interest in the identification and characterization of NSCs for therapeutic applications. However some numbers of recent studies demonstrated the existence of endogenous NSCs in adult mammalian central nerve system, their self-repairing activity is very faint. The cause of poor regenerative capability would be included microenvironmental factors that inhibit neurogenesis and axonal regeneration. We have investigated the effect of NSCs transplantation and modification the microenvironment for experimental spinal cord injury. This review will provide an overview of therapeutic strategy for neurodegenerative diseases and traumatic injury, such as Parkinson's disease and spinal cord injury.
Lymphocytes are mobile and travel from blood to lymph and then return to blood, which ensures a coordinated expression of immunological functions. In lymph nodes (LN) and Peyer's patches, the port of entry for naive T and B cells is the high endothelial venules (HEVs). The endothelial cells of HEVs are characterized by the luminal presentation of various adhesion molecules and chemokines. Some of the endothelial adhesion molecules are responsible for the tissue-specific trafficking of lymphocytes by giving lymphocytes positional cues, and hence are called vascular addressins. The peripheral LN addressins (PNAd) include several sialomucins and the mucosal LN addressin is MAdCAM-1. The complementary lymphocyte homing receptors for these addressins are L-selectin for PNAd, and α4β7 integrin for MAdCAM-1. While L-selectin and their counter-receptors are primarily involved in lymphocyte rolling along the endothelial surface, LFA-1 and its counter-receptor ICAMs are thought to be involved in firm adhesion of lymphocytes. During the course of rolling, lymphocytes are rapidly and transiently activated by chemokines expressed in HEV, which leads to rapid activation of LFA-1-mediated lymphocyte adhesion to HEV. How the subsequent transmigration of lymphocytes is controlled remains poorly characterized. Here We briefly review the molecular mechanisms controlling chemokine-driven lymphocyte trafficking across HEVs.
Granulocyte colony-stimulating factor (G-CSF) is a naturally occurring glycosylated protein that was originally identified as a granulopoietic growth factor. It has been shown that G-CSF stimulates the proliferation and maturation of neutrophil precursor cells as well as increases such neutrophil functions as chemotaxis, phagocytosis, and bactericidal activity. G-CSF has drawn recent attention as a therapeutic drug for sepsis, because studies show that G-CSF not only selectively stimulates the proliferation of neutrophils but also plays an important role as a multipotent modulator of acute inflammation. We previously reported an increased serum G-CSF concentration concomitant with an elevated absolute neutrophil count showing a left shift toward more immature forms, and that neutrophil phagocytic and bactericidal activity is maintained in patients with trauma or sepsis. We suggested that G-CSF plays an important role in neutrophil maturation and the maintenance of neutrophil function in inflammatory response associated with trauma and sepsis. We also investigated the clinical effects of recombinant human G-CSF (rhG-CSF) administration in patients with sepsis who lack appropriate neutrophilia. We concluded that rhG-CSF administration attenuates inflammatory responses without inducing tissue injury. In addition, we found the difference in responses after rhG-CSF in each patients with sepsis. In the good response group, rhG-CSF administration markedly improved the severity of illness and produced a good outcome. The endogenous G-CSF level in blood showed lower than that in the poor response patients before rhG-CSF administration. Immature neutrophils was significantly higher in poor response group than those in good response group. Those results suggest that rhG-CSF was effective in septic patients with a low percentage of immature neutrophils and insufficient endogenous G-CSF. Some recent reports, however, have suggested that rhG-CSF treatment in patients receiving cytotoxins can be associated with pulmonary toxicity. However, we revealed that rhG-CSF causes leukocyte stiffness but attenuates inflammatory response without inducing lung injury in septic patients. This review will provide an overview of our current understanding of the role of G-CSF as an anti-inflammatory modulator in patients with sepsis.
Given the current theory of inflammatory changes being involved in the progression of endometriosis, MAPKs might be at play as pivotal intracellular signal transducers in endometriotic cells and thus have a pathophysiological role in the disease. In vitro study using endometriotic cell, all the MAPK inhibitors examined suppressed IL-1β-induced secretion of IL-6 and IL-8, and IL-1β-induced expression of COX-2 in endometriotic cells. Among MAPK inhibitors, p38MAPK inhibitor seemed to have the best potential to block inflammation. Then, the authors evaluated the effect of FR 167653, a p38MAPK inhibitor, on the development of endometriotic lesions and on the intraperitoneal inflammatory status using experimental model mice for endometriosis. FR 167653, a p38 MAPK inhibitor, caused a reduction in the growth of endometriotic lesions, coupled with the suppression of intraperitoneal inflammation. Thus, p38 MAPK inhibitors could have the therapeutic potential for endometriosis.
Recent rapid development of molecular biology together with the steady progress of genome projects has been given us some essential and revolutionary informations of gene to elucidate all the biological phenomena at the molecular level. Under these circumstances, gene transfection has become one of the fundamental technologies indispensable to the basic research of medicine and biology. Human gene therapy has been performed with plasmid DNA alone or the virus vector constructs. However, there are clinical limitations, low gene expression of plasmid DNA and the immunogenicity and toxicity of virus itself or the possible mutagenesis of cells transfected. Therefore, several non-viral vectors of synthetic materials have been explored to enhance the transfection efficiency of gene into mammalian cells both in vitro and in vivo. In this paper, as one research trial, the controlled release of plasmid DNA is overviewed. A new system of plasmid DNA release with a biodegradable hydrogel is explained while the biological activity of a plasmid DNA of hepatocyte growth factor antagonist, NK4, is augmented by use of the release system.
Cell transplantation is promising therapeutic strategy for spinal cord injury (SCI). Embryonic stem (ES) cells proliferate in vitro through many passages without losing their totipotentiality and are good sources for transplantable cells. However, whether the grafted cells further differentiate into mature motoneurons and directly contribute to the reconstruction of neuronal pathway in SCI remains largely unknown. In this study, mouse ES cells were treated with retinoic acid to induce neural progenitor cells, which were transplanted to the completely transected spinal cord at T7-T8 of mice. The mice transplanted with neural progenitor cells exhibited potent functional recoveries of their hind limbs and tail, showing significant higher scores of locomotor behavioral tests compared with SCI mice having vehicle injection, and electrophysiological assessment confirmed the re-emergence of motor evoked potential of injured spinal cord. Histological analysis of injured spinal cord demonstrated that engraftment of the neural progenitor cells into a vacant spinal column cavity made by removal of the transected spinal cord, reconnected the spinal cord and large numbers of grafted cells were found alive. The grafted cells expressed neurofilament middle chain and Synaptophysin, suggesting differentiation into mature neurons and synapse formation. RT-PCR and immunohistochemical analyses demonstrated that the differentiated neurons expressed markers for motoneurons, Islet1, HB9 and Lim1/2, suggesting their differentiation into spinal motoneurons. Taken together, neural progenitor cells derived from ES cells can be successfully transplanted to injured spinal cord, survive, further differentiate into motoneurons and reconstruct neuronal pathways in vivo, resulted in functional and electrophysiological recoveries of injured spinal cord.
It is well known that prostanoids preparation is efficient for refractory dermal ulcer and arteriosclerosis obliterans (ASO). Recently, although it has been also shown that one prostanoid has a promotive action on angiogenesis, the mechanism of action is not cleared. The efficacy of an alprostadil (Lipo-PG-E1, Palux) as DDS preparation for the VEGF production by dermal fibroblasts under stimulation with the preparation was investigated in cultured fibroblasts derived from healthy skin in the present study. The dermal fibroblasts produced VEGF protein dosedependently by addition of alprostadil. The fibroblasts stimulated IL-1 also enhanced VEGF production but the production was inhibited by COX inhibitors (indomethacin and NS-398). VEGF produced by dermal fibroblasts were regulated by prostanoids. Furthermore, it was suggested that the endogenous prostanoids by dermal fibroblasts influenced the production of VEGF. These results may be able to apply alprostadil preparation (Lipo-PG-E1) to as an effective device of angiogenesis therapy by using the technique of pharmacologicalpharmaceutical regenerative medicine.