ABSTRACT
The transplantation of progenitor cells is a promising new approach for the treatment of gliomas. Marrow stromal cells (MSC) are possible candidates for such a cell-based therapy, since they are readily and autologously available and show an extensive tropism to gliomas in vitro and in vivo. However, the signals that guide the MSC are still poorly understood. In this study, we show that gliomas have the capacity to actively attract MSC by secreting a multitude of angiogenic cytokines. We demonstrate that interleukin-8 (IL-8), transforming growth factor-ss1 (TGF-ss1) and neurotrophin-3 (NT-3) contribute to this glioma-directed tropism of human MSC. Together with the finding that vascular endothelial growth factor (VEGF) is another MSC-attracting factor secreted by glioma cells, these data support the hypothesis that gliomas use their angiogenic pathways to recruit mesenchymal progenitor cells.
Subject(s)
Bone Marrow Cells/metabolism , Brain Neoplasms/metabolism , Cytokines/metabolism , Glioma/metabolism , Mesenchymal Stem Cells/metabolism , Stromal Cells/metabolism , Bone Marrow Cells/pathology , Brain Neoplasms/pathology , Cells, Cultured , Chemotaxis , Culture Media, Conditioned , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Fluorescent Antibody Technique , Glioma/pathology , Humans , Interleukin-8/metabolism , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/pathology , Neurotrophin 3/metabolism , Stromal Cells/pathology , Transforming Growth Factors/metabolism , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Application of adult bone marrow stromal cells (BMSC) improves functional outcome in animal models of cerebral ischemia, traumatic brain injury, and spinal cord injury. Accumulating evidence suggests that such functional recovery after BMSC treatment is mediated by enhanced trophic support of the injured neurons and improved neuronal plasticity rather than tissue replacement by bone marrow-derived stem cells. Therefore, the aim of the present study was to explore the potential of non-hematopoietic BMSC to stimulate signaling pathways in neurons that mediate trophic effects and neuroprotection. In primary embryonic rat neurons, BMSC conditioned medium (CM) attenuated staurosporine (STS) or amyloid-beta peptide-induced apoptosis in a concentration-dependent manner. The neuroprotective effect of CM required several hours of pretreatment and was abolished by heating over 90 degrees C. Immunoblot analyses revealed that CM enhanced Erk1/2 and Akt phosphorylation in neurons, and the specific MEK1 inhibitor PD98059 or the phosphoinositide-3 kinase (PI3-K) inhibitor Ly294002 abolished the neuroprotective effect of CM. Further, double-conditioned medium (DCM) obtained from BMSC previously stimulated by medium from STS-challenged neurons showed a more potent anti-apoptotic effect compared to the single-conditioned medium. Overall, these findings demonstrate that BMSC trigger endogenous survival signaling pathways in neurons that mediate protection against apoptotic insults. Moreover, the interaction between stressed neurons and BMSC further amplifies the observed neuroprotective effect.
Subject(s)
Bone Marrow Cells/metabolism , Mitogen-Activated Protein Kinases/metabolism , Neurons/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Stromal Cells/cytology , Animals , Bone Marrow Cells/enzymology , Cells, Cultured , Culture Media, Conditioned , Enzyme Activation , Gerbillinae , Neurons/enzymology , Rats , Rats, Sprague-DawleyABSTRACT
Human herpesvirus 6 (HHV-6), the causative agent of exanthema subitum in childhood, can also induce meningoencephalitis in immunocompromised individuals. In contrast, HHV-6 encephalitis in immunocompetent patients is rare, and the clinical syndrome not well defined. We report a case of meningoencephalitis caused by HHV-6 type B in an otherwise healthy woman.
Subject(s)
Ganciclovir/therapeutic use , Herpesvirus 6, Human/physiology , Immunocompetence , Meningoencephalitis/drug therapy , Meningoencephalitis/virology , Roseolovirus Infections/virology , Adult , Antiviral Agents/therapeutic use , Female , Herpesvirus 6, Human/isolation & purification , Humans , Meningoencephalitis/diagnosis , Roseolovirus Infections/diagnosis , Roseolovirus Infections/drug therapyABSTRACT
BACKGROUND AND PURPOSE: Graft-versus-host disease (GvHD) is a major complication after allogeneic bone marrow transplantation (BMT). The theory that the central nervous system (in addition to the peripheral nervous system) participates in GvHD has been supported by detection of cerebral lymphomononuclear infiltrates in experimental GvHD and the observation of cerebral angiitis-like disease in patients with chronic GvHD. METHODS: In a murine BMT model, we investigated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on cerebral endothelium after allogeneic and syngeneic transplantation. Through the use of ICAM-1-knockout mice, the effect of ICAM-1 deficiency on cellular infiltration was evaluated. As an indicator of enhanced apoptotic cell death, we examined the cerebral expression of Fas antigen (Fas), the occurrence of the poly-ADP ribose polymerase p85 fragment, and the distribution of TUNEL positive-stained cells. RESULTS: In close correlation with earlier findings of cerebral infiltration in the same animals, we found cerebral endothelial upregulation of ICAM-1 and especially of VCAM-1 in allogeneic recipients compared with syngeneic animals without GvHD and unmanipulated controls. In ICAM-1-knockout mice, leukocytic infiltration did not differ from that in wild-type animals. Neither cerebral histopathologic changes nor an apoptotic effect of cellular infiltrates on brain parenchyma could be detected. CONCLUSIONS: In this model of experimental GvHD, VCAM-1 may play a critical role in leukocyte recruitment into the central nervous system of animals with chronic GvHD.
Subject(s)
Brain/blood supply , Brain/metabolism , Endothelium, Vascular/metabolism , Graft vs Host Disease/metabolism , Intercellular Adhesion Molecule-1/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Animals , Apoptosis/immunology , Bone Marrow Transplantation , Brain/cytology , Cell Movement/immunology , Disease Models, Animal , Graft vs Host Disease/immunology , Humans , Immunohistochemistry , In Situ Nick-End Labeling/methods , Leukocytes, Mononuclear/immunology , Mice , Mice, Knockout , Neutrophil Infiltration/immunology , Transplantation, Homologous , Transplantation, Isogeneic , Up-Regulation , fas Receptor/metabolismABSTRACT
Bone marrow stromal cells, which normally give rise to bone, cartilage, adipose tissue, and hematopoiesis-supporting cells, have been shown to differentiate in vitro and in vivo into neural-like cells. In this study, we examined the expression of neuronal and glial markers in human marrow stromal cells under culture conditions appropriate for neural stem cells, and compared the unsorted cell population to bone marrow CD133+ stem-like cells using immunofluorescence, Western blot, and functional patch-clamp analysis. Overall, the expression of the early neuronal marker beta3-tubulin was most pronounced in the presence of DMEM/F12 and neurotrophin 3 (NT3) or brain-derived neurotrophic factor (BDNF), when marrow stromal cells were cultured onto fibronectin. Electrophysiological examination, however, could not show fast sodium currents or functional neurotransmitter receptors in differentiated marrow stromal cells. CD133+ mesenchymal stem-like cells, but not CD34+/CD133- cells, generally showed a higher expression of neuronal markers than did unsorted marrow stromal cells, and differentiated CD133+ cells more resembled neuron-like cells.
