RESUMEN
Schizophrenia has been considered a devastating clinical syndrome rather than a single disease. Nevertheless, the mechanisms behind the onset of schizophrenia have been only partially elucidated. Several studies propose that levels of trace elements are abnormal in schizophrenia; however, conflicting data generated from different biological sources prevent conclusions being drawn. In this work, we used synchrotron radiation X-ray microfluorescence spectroscopy to compare trace element levels in neural progenitor cells (NPCs) derived from two clones of induced pluripotent stem cell lines of a clozapine-resistant schizophrenic patient and two controls. Our data reveal the presence of elevated levels of potassium and zinc in schizophrenic NPCs. Neural cells treated with valproate, an adjunctive medication for schizophrenia, brought potassium and zinc content back to control levels. These results expand the understanding of atomic element imbalance related to schizophrenia and may provide novel insights for the screening of drugs to treat mental disorders.
Asunto(s)
Antipsicóticos/farmacología , Células-Madre Neurales/efectos de los fármacos , Potasio/metabolismo , Esquizofrenia/tratamiento farmacológico , Ácido Valproico/farmacología , Zinc/metabolismo , Antipsicóticos/uso terapéutico , Línea Celular , Clozapina/uso terapéutico , Resistencia a Medicamentos , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Células-Madre Neurales/metabolismo , Esquizofrenia/metabolismoRESUMEN
Müller cells constitute the main glial cell type in the retina where it interacts with virtually all cells displaying relevant functions to retinal physiology. Under appropriate stimuli, Müller cells may undergo dedifferentiation, being able to generate other neural cell types. Here, we show that purified mouse Müller cells in culture express a group of proteins related to the dopaminergic phenotype, including the nuclear receptor-related 1 protein, required for dopaminergic differentiation, as well the enzyme tyrosine hydroxylase. These dopaminergic components are active, since Müller cells are able to synthesize and release dopamine to the extracellular medium. Moreover, Müller-derived tyrosine hydroxylase can be regulated, increasing its activity because of phosphorylation of serine residues in response to agents that increase intracellular cAMP levels. These observations were extended to glial cells obtained from adult monkey retinas with essentially the same results. To address the potential use of dopaminergic Müller cells as a source of dopamine in cell therapy procedures, we used a mouse model of Parkinson's disease, in which mouse Müller cells with the dopaminergic phenotype were transplanted into the striatum of hemi-parkinsonian mice generated by unilateral injection of 6-hydroxydopamine. These cells fully decreased the apomorphine-induced rotational behavior and restored motor functions in these animals, as measured by the rotarod and the forelimb-use asymmetry (cylinder) tests. The data indicate local restoration of dopaminergic signaling in hemi-parkinsonian mice confirmed by measurement of striatal dopamine after Müller cell grafting.
Asunto(s)
Neuronas Dopaminérgicas/trasplante , Células Ependimogliales/trasplante , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/terapia , Animales , Cebus , Diferenciación Celular/fisiología , Células Cultivadas , Cuerpo Estriado/citología , Cuerpo Estriado/fisiología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/metabolismo , Células Ependimogliales/citología , Células Ependimogliales/metabolismo , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/fisiología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Trastornos Parkinsonianos/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Recuperación de la Función/fisiología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Strategies aimed at improving spinal cord regeneration after trauma are still challenging neurologists andneuroscientists throughout the world. Many cell-based therapies have been tested, with limited success in termsof functional outcome. In this study, we investigated the effects of human dental pulp cells (HDPCs) in a mousemodel of compressive spinal cord injury (SCI). These cells present some advantages, such as the ease of theextraction process, and expression of trophic factors and embryonic markers from both ecto-mesenchymal andmesenchymal components. Young adult female C57/BL6 mice were subjected to laminectomy at T9 andcompression of the spinal cord with a vascular clip for 1 min. The cells were transplanted 7 days or 28 days afterthe lesion, in order to compare the recovery when treatment is applied in a subacute or chronic phase. Weperformed quantitative analyses of white-matter preservation, trophic-factor expression and quantification, andultrastructural and functional analysis. Our results for the HDPC-transplanted animals showed better whitematterpreservation than the DMEM groups, higher levels of trophic-factor expression in the tissue, better tissueorganization, and the presence of many axons being myelinated by either Schwann cells or oligodendrocytes, inaddition to the presence of some healthy-appearing intact neurons with synapse contacts on their cell bodies. Wealso demonstrated that HDPCs were able to express some glial markers such as GFAP and S-100. The functionalanalysis also showed locomotor improvement in these animals. Based on these findings, we propose that HDPCsmay be feasible candidates for therapeutic intervention after SCI and central nervous system disorders inhumans.
Asunto(s)
Ratas , Laminectomía/métodos , Laminectomía/rehabilitación , Neuroglía/fisiología , Pulpa Dental/trasplante , Receptores de Factores de Crecimiento , Traumatismos de la Médula Espinal/diagnóstico , Traumatismos de la Médula Espinal/rehabilitación , Células de Schwann , Microscopía Electrónica/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/métodosRESUMEN
Strategies aimed at improving spinal cord regeneration after trauma are still challenging neurologists and neuroscientists throughout the world. Many cell-based therapies have been tested, with limited success in terms of functional outcome. In this study, we investigated the effects of human dental pulp cells (HDPCs) in a mouse model of compressive spinal cord injury (SCI). These cells present some advantages, such as the ease of the extraction process, and expression of trophic factors and embryonic markers from both ecto-mesenchymal and mesenchymal components. Young adult female C57/BL6 mice were subjected to laminectomy at T9 and compression of the spinal cord with a vascular clip for 1 min. The cells were transplanted 7 days or 28 days after the lesion, in order to compare the recovery when treatment is applied in a subacute or chronic phase. We performed quantitative analyses of white-matter preservation, trophic-factor expression and quantification, and ultrastructural and functional analysis. Our results for the HDPC-transplanted animals showed better white-matter preservation than the DMEM groups, higher levels of trophic-factor expression in the tissue, better tissue organization, and the presence of many axons being myelinated by either Schwann cells or oligodendrocytes, in addition to the presence of some healthy-appearing intact neurons with synapse contacts on their cell bodies. We also demonstrated that HDPCs were able to express some glial markers such as GFAP and S-100. The functional analysis also showed locomotor improvement in these animals. Based on these findings, we propose that HDPCs may be feasible candidates for therapeutic intervention after SCI and central nervous system disorders in humans.
Asunto(s)
Trasplante de Células/métodos , Pulpa Dental/trasplante , Fibras Nerviosas Mielínicas/patología , Recuperación de la Función/fisiología , Compresión de la Médula Espinal/terapia , Médula Espinal/patología , Animales , Axones/patología , Pulpa Dental/citología , Femenino , Humanos , Ratones , Modelos Animales , Actividad Motora/fisiología , Neuroglía/patología , Neuronas/patología , Médula Espinal/fisiopatología , Compresión de la Médula Espinal/patología , Compresión de la Médula Espinal/fisiopatología , Resultado del TratamientoRESUMEN
We tested the effects of mouse embryonic stem cells (mES) grafts in mice spinal cord injury (SCI). Young adult female C57/Bl6 mice were subjected to laminectomy at T9 and 1-minute compression of the spinal cord with a vascular clip. Four groups were analyzed: laminectomy (Sham), injured (SCI), vehicle (DMEM), and mES-treated (EST). mES pre-differentiated with retinoic acid were injected (8 x 10(5) cells/2 microl) into the lesion epicenter, 10 min after SCI. Basso mouse scale (BMS) and Global mobility test (GMT) were assessed weekly up to 8 weeks, when morphological analyses were performed. GMT analysis showed that EST animals moved faster (10.73+/-0.9076, +/-SEM) than SCI (5.581+/-0.2905) and DMEM (5.705+/-0.2848), but slower than Sham animals (15.80+/-0.3887, p<0.001). By BMS, EST animals reached the final phase of locomotor recovery (3.872+/-0.7112, p<0.01), while animals of the SCI and DMEM groups improved to an intermediate phase (2.037+/-0.3994 and 2.111+/-0.3889, respectively). White matter area and number of myelinated nerve fibers were greater in EST (46.80+/-1.24 and 279.4+/-16.33, respectively) than the SCI group (39.97+/-0.925 and 81.39+/-8.078, p<0.05, respectively). EST group also presented better G-ratio values when compared with SCI group (p<0.001). Immunohistochemical revealed the differentiation of transplanted cells into astrocytes, oligodendrocytes, and Schwann cells, indicating an integration of transplanted cells with host tissue. Ultrastructural analysis showed, in the EST group, better tissue preservation and more remyelination by oligodendrocytes and Schwann cells than the other groups. Our results indicate that acute transplantation of predifferentiated mES into the injured spinal cord increased the spared white matter and number of nerve fibers, improving locomotor function.