Neuroglial components of brain lesions may provide new therapeutic strategies for multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune and demyelinating disease of the central nervous system (CNS) which leads to focal demyelinated lesions in the brain and spinal cord. Failure of remyelination contributes to chronic disability in young adults. Characterization of events occurring during the demyelination and remyelination processes and those of which subsequently limit remyelination or contribute to demyelination can provide the possibility of new therapies development for MS. Most of the currently available therapies and investigations modulate immune responses and mediators. Since most therapeutic strategies have unsatisfied outcomes, developing new therapies that enhance brain lesion repair is a priority. A close look at cellular and chemical components of MS lesions will pave the way to a better understanding of lesions pathology and will provide possible opportunities for repair strategies and targeted pharmacotherapy. This review summarizes the lesion components and features, particularly the detrimental elements, and discusses the possibility of suggesting new potential targets as therapies for demyelinating diseases like MS.

Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.

Dominant mutations in tyrosyl-tRNA synthetase (YARS1) and six other tRNA ligases cause Charcot-Marie-Tooth peripheral neuropathy (CMT). Loss of aminoacylation is not required for their pathogenicity, suggesting a gain-of-function disease mechanism. By an unbiased genetic screen in Drosophila, we link YARS1 dysfunction to actin cytoskeleton organization. Biochemical studies uncover yet unknown actin-bundling property of YARS1 to be enhanced by a CMT mutation, leading to actin disorganization in the Drosophila nervous system, human SH-SY5Y neuroblastoma cells, and patient-derived fibroblasts. Genetic modulation of F-actin organization improves hallmark electrophysiological and morphological features in neurons of flies expressing CMT-causing YARS1 mutations. Similar beneficial effects are observed in flies expressing a neuropathy-causing glycyl-tRNA synthetase. Hence, in this work, we show that YARS1 is an evolutionary-conserved F-actin organizer which links the actin cytoskeleton to tRNA-synthetase-induced neurodegeneration.

Fingolimod Enhances Oligodendrocyte Differentiation of Transplanted Human Induced Pluripotent Stem Cell-Derived Neural Progenitors.

Multiple sclerosis (MS) is an autoimmune disease which affects myelin in the central nervous system (CNS) and leads to serious disability. Currently available treatments for MS mainly suppress the immune system. Regenerative medicine-based approaches attempt to increase myelin repair by targeting endogenous progenitors or transplanting stem cells or their derivatives. Fingolimod exerts anti-inflammatory effects and directly affects neural cells. In this study we assessed the effect of fingolimod on transplanted human induced pluripotent stem cell derived neural progenitors (hiPSC-NPs). hiPSC-NPs were labeled by green fluorescence protein (GFP) and transplanted into the corpus callosum of mice which were chronically demyelinated after cuprizone (CPZ) feedings for 10 weeks. The animals received fingolimod from 1 day prior to NPs transplantation via gavage as well as daily intraperitoneal cyclosporine A from 2 days before cell transplantation until the time of sampling. At either 7 or 21 days after NPs transplantation, the animals were sacrificed and their brains were histologically evaluated for the number of transplanted cells and their fate. In the animals treated with fingolimod, we observed higher numbers of NPs within the injection site compared to the animals who did not receive fingolimod showing that hiPSC- NPs were more efficiently differentiated to the oligodendrocyte lineage. These data have suggested that repetitive treatment with fingolimod, beside its anti-inflammatory effect, may enhance the survival and differentiation of transplanted NPs to oligodendrocyte lineage cells to participate in myelin repair.

In vivo conversion of astrocytes into oligodendrocyte lineage cells with transcription factor Sox10; Promise for myelin repair in multiple sclerosis.

Recent studies demonstrate that astroglial cells can be directly converted into functional neurons or oligodendrocytes. Here, we report that a single transcription factor Sox10 could reprogram astrocytes into oligodendrocyte-like cells, in vivo. For transdifferentiation, Sox10-GFP expressing viral particles were injected into cuprizone-induced demyelinated mice brains after which we assessed for the presence of specific oligodendrocyte lineage cell markers by immunohistofluorescence (IHF). As control, another group of demyelinated mice received GFP expressing viral particles. After 3 weeks, the majority of transduced (GFP+) cells in animals which received control vector were astrocytes, while in animals which received Sox10-GFP vector, the main population of GFP+ cells were positive for oligodendrocyte lineage markers. We also extracted primary astrocytes from mouse pups and purified them. Primary astrocytes were transduced in vitro and then transplanted into demyelinated brains for later fate mapping. After three weeks, in vitro transduced and then transplanted astrocytes showed oligodendrocyte progenitor and mature oligodendrocyte markers. Further confirmation was done by transduction of astrocytes with lentiviral particles that expressed Sox10 and GFP and their culture in the oligodendrocyte progenitor medium. The induced cells expressed oligodendrocyte progenitor cells (iOPCs) markers. Our findings showed the feasibility of reprogramming of astrocytes into oligodendrocyte-like cells in vivo, by using a single transcription factor, Sox10. This finding suggested a master regulatory role for Sox10 which enabled astrocytes to change their fate to OPC-like cells and establish an oligodendroglial phenotype. We hope this approach lead to effective myelin repair in patients suffering from myelination deficit.

Activation of TGFß1 signaling enhances early dopaminergic differentiation in unrestricted somatic stem cells.

So far there is increasing evidence for the involvement of transforming growth factor beta TGFß (transforming growth factor) in differentiation and maintenance of midbrain dopaminergic neurons. Considering that USSCs (unrestricted somatic stem cells) have the potentials to differentiate into neuron-like cells and even dopaminergic neurons and that no evidence available on the role of TGFß signaling in dopaminergic differentiation of these cells, we investigated the presence of TGFß signaling components in USSCs and their involvement on USSCs differentiation into early dopaminergic neurons. Our results showed that components of TGFß signaling were present and functional in undifferentiated USSCs, after which the neurally induced USSCs treated with TGFß1 for 3 days resulted in increased expression of ß-tubulin III (a general neuronal marker) and Nurr-1 (an early dopaminergic marker) at both mRNA and protein levels. Consistently, TGFß inhibition in culture medium by using SB431542 in the presence or absence of TGFß1, significantly decreased the expression of both neural markers. We therefore suggest that activation of TGFß signaling-pathway in neurally induced USSCs enhances neural differentiation with an early dopaminergic phenotype which points at the positive role of the TGFß signaling pathway toward dopaminergic fate.