Bone marrow mesenchymal stem cells (MSCs) can differentiate into several types of mesenchymal cells, including osteocytes, chondrocytes, and adipocytes, but, under appropriate experimental conditions, can also differentiate into nonmesenchymal cells-for instance, neural cells. These observations have raised interest in the possible use of MSCs in cell therapy strategies for various neurological disorders. In the study reported here, we addressed the question of in vitro differentiation of MSCs into functional neurons. First, we demonstrate that when they are co-cultured with cerebellar granule neurons, adult MSCs can express neuronal markers. Two factors are needed for the emergence of neuronal differentiation of the MSCs: the first one is nestin expression by MSCs (nestin is a marker for the responsive character of MSCs to extrinsic signals), and the second one is a direct cell-cell interaction between neural cells and MSCs that allows the integration of these extrinsic signals. Three different approaches suggest that neural phenotypes arise from MSCs by a differentiation rather than a cell fusion process, although this last phenomenon can also coexist. The expression of several genes-including sox, pax, notch, delta, frizzled, and erbB-was analyzed by quantitative reverse transcription polymerase chain reaction (RT-PCR) in order to further characterize the nestin-positive phenotype compared to the nestin-negative one. An overexpression of sox2, sox10, pax6, fzd, erbB2, and erbB4 is found in nestin-positive MSCs. Finally, electrophysiological analyses demonstrate that MSC-derived neuron-like cells can fire single-action potentials and respond to several neurotransmitters such as GABA, glycine, and glutamate. We conclude that nestin-positive MSCs can differentiate in vitro into excitable neuron-like cells. Stem Cells 2005;23:392-402

During brain ontogenesis, the temporal and spatial generation of the different types of neuronal and glial cells from precursors occurs as a sequence of successive progenitor stages whose proliferation, survival and cell-fate choice are controlled by environmental and cellular regulatory molecules. Neurotransmitters belong to the chemical microenvironment of neural cells, even at the earliest stages of brain development. It is now established that specific neurotransmitter receptors are present on progenitor cells of the developing central nervous system and could play, during neural development, a role that has remained unsuspected until recently. The present review focuses on the occurrence of neurotransmitters and their corresponding ligand-gated ion channel receptors in immature cells, including neural stem cells of specific embryonic and neonatal brain regions. We summarize in vitro and in vivo data arguing that neurotransmitters could regulate morphogenetic events such as proliferation, growth, migration, differentiation and survival of neural precursor cells. The understanding of neurotransmitter function during early neural maturation could lead to the development of pharmacological tools aimed at improving adult brain repair strategies.

Eccentric contractions, characterized by the lengthening of the muscle-tendon complex, present several unique features compared with other types of contractions, which may lead to unique adaptations. Due to its specific physiological and mechanical properties, there is an increasing interest in employing eccentric muscle work for rehabilitation and clinical purposes. However, unaccustomed eccentric exercise is known to cause muscle damage and delayed pain, commonly defined as “Delayed-Onset Muscular Soreness” (DOMS). To date, the most useful preventive strategy to avoid these adverse effects consists of repeating sessions involving submaximal eccentric contractions whose intensity is progressively increased over the training. Despite an increased number of investigations focusing on the eccentric contraction, a significant gap still remains in our understanding of the cellular and molecular mechanisms underlying the initial damage response and subsequent adaptations to eccentric exercise. Yet, unraveling the molecular basis of exercise-related muscle damage and soreness might help uncover the mechanistic basis of pathological conditions as myalgia or neuromuscular diseases. In addition, a better insight into the mechanisms governing eccentric training adaptations should provide invaluable information for designing therapeutic interventions and identifying potential therapeutic targets.

Radial glial cells are characterized, besides their astroglial properties,by long radial processes extending from the ventricular zone to the pial surface, a crucial feature for the radial migration of neurons. The molecular signals that regulate this characteristic morphology, however, are largely unknown. We show an important role of the secreted molecule reelin for the establishment of radial glia processes. We describe a significant reduction in ventricular zone cells with long radial processes in the absence of reelin in the cortex of reeler mutant mice. These defects were correlated to a decrease in the content of brain lipid-binding protein (Blbp) and were detected exclusively in the cerebral cortex, but not in the basal ganglia of reeler mice. Conversely, reelin addition in vitro increased the Blbp content and process extension of radial glia from the cortex, but not the basal ganglia. Isolation of radial glia by fluorescent-activated cell sorting showed that these effects are due to direct signaling of reelin to radial glial cells. We could further demonstrate that this signaling requires Dab1, as the increase in Blbp upon reelin addition failed to occur in Dab1-/-mice. Taken together, these results unravel a novel role of reelin signaling to radial glial cells that is crucial for the regulation of their Blbp content and characteristic morphology in a region-specific manner.

1 In this study in vitro and in vivo approaches were combined in order to investigate if the antiepileptic mechanism(s) of action of levetiracetam (LEV; Keppra 1 ) may involve modulation of inhibitory neurotransmission. 2 GABA-and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured cerebellar granule, hippocampal and spinal neurons. Protection against clonic convulsions was assessed in vivo in sound-susceptible mice. The eect of LEV was compared with reference anti-epileptic drugs (AEDs): carbamazepine, phenytoin, valproate, clonazepam, phenobarbital and ethosuximide. 3 LEV contrasted the reference AEDs by an absence of any direct eect on glycine-gated currents. At high concentrations, beyond therapeutic relevance, it induced a small reduction in the peak amplitude and a prolongation of the decay phase of GABA-gated currents. A similar action on GABA-elicited currents was observed with the reference AEDs, except ethosuximide. 4 These minor direct eects contrasted with a potent ability of LEV (EC 50 =1 ± 10 mM) to reverse the inhibitory eects of the negative allosteric modulators zinc and b-carbolines on both GABA A and glycine receptor-mediated responses. . In contrast, the benzodiazepine receptor antagonist¯umazenil (up to 10 mg kg 71) was without any eect on the protection aorded by LEV. 7 The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the antiepileptic mechanism(s) of action of LEV.