ABSTRACT
SUMMARY STATEMENT: NG2-glia alters its dynamics in response to L-DOPA-induced dyskinesia. In these animals, striatal NG2-glia density was reduced with cells presenting activated phenotype while doxycycline antidyskinetic therapy promotes a return to NG2-glia cell density and protein to a not activated state.
Subject(s)
Dyskinesia, Drug-Induced , Parkinsonian Disorders , Rats , Animals , Levodopa/adverse effects , Antiparkinson Agents/adverse effects , Doxycycline/therapeutic use , Rats, Sprague-Dawley , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/chemically induced , Dyskinesia, Drug-Induced/drug therapy , Neuroglia/metabolism , Oxidopamine , Disease Models, AnimalABSTRACT
Sulfatides are sulfoglycolipids found in the myelin sheath. The composition ratio of sulfatide molecular species changes with age, and it has also been associated with the pathogenesis of various human central nervous system diseases. However, profiling sulfatides in biological samples is difficult, due to the great variety of molecular species. In this work, a new, easy and reliable liquid chromatography-electrospray tandem mass spectrometry (LC-ESI(+)-MS/MS) method has been developed to profile sulfatide content in biological samples of myelin. The 'wrong-way-round' ionization effect has been described for this type of molecules for the first time, making it possible to correctly identify as many as 37 different sulfatides in mouse brain myelin samples, including molecules with different fatty acid chain lengths and varying degrees of unsaturation and hydroxylation. A chemometric analysis of their relative abundances showed that the main difference among individuals of different ages was the content of sulfatides with odd-numbered fatty acid chains, in addition to hydroxylated species.
Subject(s)
Brain Chemistry , Chromatography, Liquid , Myelin Sheath/chemistry , Sulfoglycosphingolipids/analysis , Tandem Mass Spectrometry , Aging , Animals , Mice , Mice, Inbred C57BL , Spectrometry, Mass, Electrospray IonizationABSTRACT
The importance of astrocyte heterogeneity came out as a hot topic in neurosciences especially over the last decades, when the development of new methodologies allowed demonstrating the existence of big differences in morphological, neurochemical and physiological features between astrocytes. However, although the knowledge about the biology of astrocytes is increasing rapidly, an important characteristic that remained unexplored, until the last years, has been the relationship between astrocyte lineages and cell heterogeneity. To fill this gap, a new method called StarTrack was recently developed, a powerful genetic tool that allows tracking astrocyte lineages forming cell clones. Using StarTrack, a single astrocyte progenitor and its progeny can be specifically labeled from its generation, during embryonic development, to its final fate in the adult brain. Because of this specific labeling, astrocyte clones, exhibiting heterogeneous morphologies and features, can be easily analyzed in relation to their ontogenetic origin. This review summarizes how astrocyte heterogeneity can be decoded studying the embryonic development of astrocyte lineages and their clonal relationship. Finally, we discuss about some of the challenges and opportunities emerging in this exciting area of investigation.
Subject(s)
Astrocytes/physiology , Cell Lineage/physiology , Genetic Techniques , Animals , Brain/growth & development , Brain/physiology , Brain/physiopathology , Cell Lineage/genetics , Humans , Neural Stem Cells/physiologyABSTRACT
During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5-7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS.
Subject(s)
Cerebral Cortex/enzymology , Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Oligodendroglia/drug effects , Adult , Animals , Cell Differentiation , Cell Proliferation , Cell Survival , Central Nervous System/metabolism , Cyclic AMP/metabolism , Epilepsy/metabolism , Humans , Mice , Microscopy, Fluorescence , Middle Aged , Multiple Sclerosis/metabolism , Oligodendroglia/cytology , Phenotype , Signal TransductionABSTRACT
INTRODUCTION: Oligodendrocyte precursor cells are generated within specific domains in the neural tube, and from there they migrate to their final destination. Once this is reached, they will differentiate into adult oligodendrocytes, which are the cells responsible for myelination in the central nervous system. The oligodendrocyte precursors conserve a certain capacity to proliferate and have an important capacity to migrate in response to specific signals. A number of different signals are involved in the migration of these cells, although they can be divided fundamentally into two groups: adhesion molecules and secretable molecules. DEVELOPMENT: Data concerning the known effects of different molecules involved in the migration of oligodendrocyte precursor cells were collected. It is also suggested that these molecules could be useful for developing new therapies to treat demyelinating diseases such as multiple sclerosis. CONCLUSIONS: Knowledge of the signals that guide the migration of oligodendrocyte precursors during the development is a tool that would make it possible to direct the migration of oligodendrocyte precursor cells to demyelinating lesions and, once they are there, to get them to proliferate and myelinate the lesion.
Subject(s)
Oligodendroglia , Animals , Cell Adhesion , Cell Lineage , Cell Movement , Chemokines/physiology , Demyelinating Diseases/surgery , Humans , Intercellular Signaling Peptides and Proteins/physiology , Membrane Proteins/physiology , Mice , Mice, Knockout , Oligodendroglia/cytology , Oligodendroglia/physiology , Oligodendroglia/transplantation , Receptors, Cell Surface/physiology , Signal Transduction , Stem Cell Transplantation , Stem Cells/physiologyABSTRACT
Los precursores de oligodendrocitos se generan en dominios específicos del tubo neural, desde dondemigran a sus destinos finales. Una vez allí, se diferenciarán a oligodendrocitos maduros, las células mielinizantes del sistema nervioso central. Los precursores de oligodendrocitos conservan cierta capacidad proliferativa y tienen gran capacidadmigratoria en respuesta a diversas señales. Existen diversas señales involucradas en la migración de estas células, aunque se podrían dividir en dos grupos: moléculas de adhesión y moléculas secretables. Desarrollo. Se recopilan los efectos conocidosde diferentes moléculas involucradas en la migración de precursores de oligodendrocitos. También se plantea la posible utilidad de estas moléculas en el desarrollo de nuevas terapias para el tratamiento enfermedades desmielinizantes, como la esclerosismúltiple. Conclusión. El conocimiento de las señales que guían la migración de los precursores de oligodendrocitos durante el desarrollo es una herramienta que permitiría dirigir la migración de los precursores de oligodendrocitos hasta las lesionesdesmielinizantes y, una vez allí, conseguir que proliferen y mielinicen la lesión
Oligodendrocyte precursor cells are generated within specific domains in the neural tube, and fromthere they migrate to their final destination. Once this is reached, they will differentiate into adult oligodendrocytes, which are the cells responsible for myelination in the central nervous system. The oligodendrocyte precursors conserve a certaincapacity to proliferate and have an important capacity to migrate in response to specific signals. A number of different signals are involved in the migration of these cells, although they can be divided fundamentally into two groups: adhesion molecules and secretable molecules. Development. Data concerning the known effects of different molecules involved in the migration of oligodendrocyte precursor cells were collected. It is also suggested that these molecules could be useful for developing new therapies to treat demyelinating diseases such as multiple sclerosis. Conclusions. Knowledge of the signals that guide the migration of oligodendrocyte precursors during the development is a tool that would make it possible to direct the migration of oligodendrocyte precursor cells to demyelinating lesions and, once they are there, to get them to proliferate and myelinate the lesion
