Mesenchymal stem cells (MSCs), also known as stromal mesenchymal stem cells, are multipotent cells, which can be found in many tissues and organs as bone marrow, adipose tissue and other tissues. In particular MSCs derived from Adipose tissue (ADSCs) are the most frequently used in regenerative medicine because they are easy to source, rapidly expandable in culture and excellent differentiation potential into adipocytes, chondrocytes, and other cell types. Acetylcholine (ACh), the most important neurotransmitter in Central nervous system (CNS) and peripheral nervous system (PNS), plays important roles also in non-neural tissue, but its functions in MSCs are still not investigated. Although MSCs express muscarinic receptor subtypes, their role is completely unknown. In the present work muscarinic cholinergic effects were characterized in rat ADSCs. Analysis by RT-PCR demonstrates that ADSCs express M1-M4 muscarinic receptor subtypes, whereas M2 is one of the most expressed subtype. For this reason, our attention was focused on M2 subtype. By using the selective M2 against Arecaidine Propargyl Ester (APE) we performed cell proliferation and migration assays demonstrating that APE causes cell growth and migration inhibition without affecting cell survival. Our results indicate that ACh via M2 receptors, may contribute to the maintaining of the ADSCs quiescent status. These data are the first evidence that ACh, via muscarinic receptors, might contribute to control ADSCs physiology.

The mechanisms regulating the differentiation into non-myelinating Schwann cells is not completely understood. Recent evidence indicates that GABA-B receptors may regulate myelination and nociception in the peripheral nervous system. GABA-B receptor total knock-out mice exhibit morphological and molecular changes in peripheral myelin. The number of small myelinated fibers is higher and associated with altered pain sensitivity. Herein, we analyzed whether these changes may be produced by a specific deletion of GABA-B receptors in Schwann cells. The conditional mice (P0-GABA-B1(fl/fl)) show a morphological phenotype characterized by a peculiar increase in the number of small unmyelinated fibers and Remak bundles, including nociceptive C-fibers. The P0-GABA-B1(fl/fl) mice are hyperalgesic and allodynic. In these mice, the morphological and behavioral changes are associated with a downregulation of neuregulin 1 expression in nerves. Our findings suggest that the altered pain sensitivity derives from a Schwann cell-specific loss of GABA-B receptor functions, pointing to a role for GABA-B receptors in the regulation of Schwann cell maturation towards the non-myelinating phenotype.

The Official Journal of the International Society for Neurochemistry JNC wileyonlinelibrary.com/journal/jnc The Official Journal of the International Society for Neurochemistry JNC Front cover: Confocal microscopy image of in vitro co-culture of Schwann cells and dorsal root ganglia (DRG) neurons, treated with the neuroactive steroid allopregnanolone (ALLO). Immunofluorescent labelling of Schwann cells and DRG neurite was performed with specific markers anti-myelin basic protein (green) and anti-neurofilament H (SMI31 in red), respectively; nuclei are stained with DAPI, in blue. A 21-days treatment of co-cultures with ALLO 10-6 M stimulates in vitro myelination, as shown by the merge colocalization in yellow. Overall, we proved that ALLO is active in regulating Schwann cells biological functions, such as proliferation, motility, morphological rearrangements and also myelina-tion. These actions are GABA-A receptor mediated and involve the activation of Src and phospho-FAK kinases (see Melfi S. et al. this issue). The comprehension of these mechanisms may be of potential interest to develop new therapies for the peripheral neuropathies. We wish to thank Dr. Deborah Colleoni for the assistance for image preparation. Read the full article 'Src and phospho-FAK kinases are activated by allopregnanolone promoting Schwann cell motility, morphology and myelination' by S. Melfi, M. M. Montt Guevara, V. Bonalume, M. Ruscica, A. Colciago, T. Simoncini and V. Magnaghi (J.

The development, maturation and regeneration of Schwann cells (SCs), the main glial cells of the peripheral nervous system, require the coordinate and complementary interaction among several factors, signals and intracellular pathways. These regulatory molecules consist of integrins, neuregulins, growth factors, hormones, neurotransmitters, as well as entire intracellular pathways including protein-kinase A, C, Akt, Erk/MAPK, Hippo, mTOR, etc. For instance, Hippo pathway is overall involved in proliferation, apoptosis, regeneration and organ size control, being crucial in cancer proliferation process. In SCs, Hippo is linked to merlin and YAP/TAZ signaling and it seems to respond to mechanic/physical challenges. Recently, among factors regulating SCs, also the signaling intermediates Src tyrosine kinase and focal adhesion kinase (FAK) proved relevant for SC fate, participating in the regulation of adhesion, motility, migration and in vitro myelination. In SCs, the factors Src and FAK are regulated by the neuroactive steroid allopregnanolone, thus corroborating the importance of this steroid in the control of SC maturation. In this review, we illustrate some old and novel signaling pathways modulating SC biology and functions during the different developmental, mature and regenerative states

Previous evidence showed mutations of the neurofibromin type 2 gene (Nf2), encoding the tumor suppressor protein merlin, in sporadic and vestibular schwannomas affecting Schwann cells (SCs). Accordingly, efforts have been addressed to identify possible factors, even environmental, that may regulate neurofibromas growth. In this context, we investigated the exposure of SC to an electromagnetic field (EMF), which is an environmental issue modulating biological processes. Here, we show that SC exposed to 50 Hz EMFs changes their morphology, proliferation, migration and myelinating capability. In these cells, merlin is downregulated, leading to activation of two intracellular signaling pathways, ERK/AKT and Hippo. Interestingly, SC changes their phenotype toward a proliferative/migrating state, which in principle may be pathologically relevant for schwannoma development.

These findings show that a single cocaine injection is sufficient to produce enduring changes in the adolescent brain and indicate that early cocaine priming alters the mechanisms regulating the trophic response in a brain region-specific fashion.

GABA-B receptors are important for Schwann cell (SC) commitment to a non-myelinating phenotype during development. However, the P0-GABA-B1 conditional knockout mice, lacking the GABA-B1 receptor specifically in SCs, also presented axon modifications, suggesting SC non-autonomous effects through the neuronal compartment. In this in vitro study, we evaluated whether the specific deletion of the GABA-B1 receptor in SCs may induce autonomous or non-autonomous cross-changes in sensory dorsal root ganglia (DRG) neurons. To this end, we performed an in vitro biomolecular and transcriptomic analysis of SC and DRG neuron primary cultures from P0-GABA-B1 mice. We found that cells from conditional P0-GABA-B1 mice exhibited proliferative, migratory and myelinating alterations. Moreover, we found transcriptomic changes in novel molecules that are involved in peripheral neuron-SC interaction.

No abstract