Les facteurs neurotrophiques : un mythe thérapeutique ?

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From Neural Crest Development to Cancer and Vice Versa: How p75NTR and (Pro)neurotrophins Could Act on Cell Migration and Invasion?

The p75 neurotrophin receptor (p75NTR), also known as low-affinity nerve growth factor, belongs to the tumor necrosis factor family of receptors. p75NTR is widely expressed in the nervous system during the development, as well as, in the neural crest population, since p75NTR has been described as ubiquitously expressed and considered as a neural crest marker. Neural crest cells (NCCs) constitute an transient population accurately migrating and invading, with precision, defined sites of the embryo. During migration, NCCs are guided along distinct migratory pathways by specialized molecules present in the extracellular matrix or on the surfaces of those cells. Two main processes direct NCC migration during the development: (1) an epithelial-to-mesenchymal transition and (2) a process known as contact inhibition of locomotion. In adults, p75NTR remains expressed by NCCs and has been identified in an increasing number of cancer cells. Nonetheless, the regulation of the expression of p75NTR and the underlying mechanisms in stem cell biology or cancer cells have not yet been sufficiently addressed. The main objective of this review is therefore to analyze elements of our actual knowledge regarding p75NTR roles during the development (mainly focusing on neural crest development) and see how we can transpose that information from development to cancer (and vice versa) to better understand the link between p75NTR and cell migration and invasion. In this review, we successively analyzed the molecular mechanisms of p75NTR when it interacts with several coreceptors and/or effectors. We then analyzed which signaling pathways are the most activated or linked to NCC migration during the development. Regarding cancer, we analyzed the described molecular pathways underlying cancer cell migration when p75NTR was correlated to cancer cell migration and invasion. From those diverse sources of information, we finally summarized potential molecular mechanisms underlying p75NTR activation in cell migration and invasion that could lead to new research areas to develop new therapeutic protocols

Quels espoirs de remyélinisation dans la sclérose en plaques ?

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Neuregulin-1 modulates the differentiation of neural stem cells in vitro trough an interaction with the Swi/Snf complex.

The neuregulin-1 (Nrg-1) gene is translated into several protein isoforms, which are either secreted or membrane-anchored. In vitro, neural stem cells (NSC) express mainly the cystein-rich-domain NRG (CRD-NRG) isoform, a membrane-anchored type III form. This isoform exhibits a cystein-rich-domain, which constitutes a second transmembrane domain and can be cleaved to release both a signaling EGF-containing domain (ECD) at the cell surface and an intracellular domain (ICD). The main goal of this paper was to determine the exact role of ECD and ICD in NSC survival and differentiation. Using an siRNA approach, we demonstrated that CRD-NRG inhibition was followed by a decrease in NSC proliferation and of neuronal or oligodendroglial differentiation. Overexpression of ICD but not ECD was followed by a decrease in NSC proliferation and an increase in neuronal and oligodendroglial differentiation. Moreover, we showed that ICD physically interacted in cultured NSC with BRM and BAF57, two members of the Swi/Snf remodeling complex, and that ICD stimulation of neuronal cell differentiation is dependent on the presence of BAF57

Adult Bone Marrow: Which Stem Cells for Cellular Therapy Protocols in Neurodegenerative Disorders?

The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crests (NCSCs) might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSCs). In this paper, we will review all information available concerning NCSC from adult tissues and their possible use in regenerative medicine. Moreover, as multiple recent studies showed the beneficial effect of bone marrow stromal cells in neurodegenerative diseases, we will discuss which stem cells isolated from adult bone marrow should be more suitable for cell replacement therapy

Medication-Related Osteonecrosis of the Jaw: New Insights into Molecular Mechanisms and Cellular Therapeutic Approaches

peer reviewedIn recent years, medication-related osteonecrosis of the jaw (MRONJ) became an arising disease due to the important antiresorptive drug prescriptions to treat oncologic and osteoporotic patients, as well as the use of new antiangiogenic drugs such as VEGF antagonist. So far, MRONJ physiopathogenesis still remains unclear. Aiming to better understand MRONJ physiopathology, the first objective of this review would be to highlight major molecular mechanisms that are known to be involved in bone formation and remodeling. Recent development in MRONJ pharmacological treatments showed good results; however, those treatments are not curative and could have major side effects. In parallel to pharmacological treatments, MSC grafts appeared to be beneficial in the treatment of MRONJ, in multiple aspects: (1) recruitment and stimulation of local or regional endogenous cells to differentiate into osteoblasts and thus bone formation, (2) beneficial impact on bone remodeling, and (3) immune-modulatory properties that decrease inflammation. In this context, the second objective of this manuscript would be to summarize the molecular regulatory events controlling osteogenic differentiation, bone remodeling, and osteoimmunology and potential beneficial effects of MSC related to those aspects, in order to apprehend MRONJ and to develop new therapeutic approaches

Regulation of nestin expression by thrombin and cell density in cultures of bone mesenchymal stem cells and radial glial cells

BACKGROUND: Bone marrow stromal cells and radial glia are two stem cell types with neural phenotypic plasticity. Bone marrow mesenchymal stem cells can differentiate into osteocytes, chondrocytes and adipocytes, but can also differentiate into non-mesenchymal cell, i.e. neural cells in appropriate in vivo and in vitro experimental conditions. Likewise, radial glial cells are the progenitors of many neurons in the developing cortex, but can also generate astrocytes. Both cell types express nestin, an intermediate filament protein which is the hallmark of neural precursors. RESULTS: In this study, we demonstrate that thrombin, a multifunctional serine protease, stimulates the growth of radial glial cells (RG) and mesenchymal stem cells (MSCs) in a dose-dependent manner. In RG, the mitogenic effect of thrombin is correlated with increased expression of nestin but in MSCs, this mitogenic effect is associated with nestin down-regulation. Both cell types express the PAR-1 type receptor for Thrombin and the effect of Thrombin on both cell types can be mimicked by its analogue TRAP-6 activating specifically this receptor subtype or by serum which contains various amount of thrombin. Moreover, we also demonstrate that serum deprivation-induced expression of nestin in MSCs is inhibited by high cell density (> 50,000 cells/cm2). CONCLUSION: This work shows that thrombin stimulates the growth of both RG and MSCs and that nestin expression by MSCs and RG is regulated in opposite manner by thrombin in vitro. Thrombin effect is thus associated in both cell types with a proliferating, undifferentiated state but in RG this involves the induction of nestin expression, a marker of immaturity for neural progenitors. In MSCs however, nestin expression, as it corresponds to a progression from the mesenchymal "undifferentiated", proliferating phenotype toward acquisition of a neural fate, is inhibited by the mitogenic signal

Nestin-positive mesenchymal stem cells favour the astroglial lineage in neural progenitors and stem cells by releasing active BMP4

BACKGROUND: Spontaneous repair is limited after CNS injury or degeneration because neurogenesis and axonal regrowth rarely occur in the adult brain. As a result, cell transplantation has raised much interest as potential treatment for patients with CNS lesions. Several types of cells have been considered as candidates for such cell transplantation and replacement therapies. Foetal brain tissue has already been shown to have significant effects in patients with Parkinson's disease. Clinical use of the foetal brain tissue is, however, limited by ethical and technical problems as it requires high numbers of grafted foetal cells and immunosuppression. Alternatively, several reports suggested that mesenchymal stem cells, isolated from adult bone marrow, are multipotent cells and could be used in autograft approach for replacement therapies. RESULTS: In this study, we addressed the question of the possible influence of mesenchymal stem cells on neural stem cell fate. We have previously reported that adult rat mesenchymal stem cells are able to express nestin in defined culture conditions (in the absence of serum and after 25 cell population doublings) and we report here that nestin-positive (but not nestin-negative) mesenchymal stem cells are able to favour the astroglial lineage in neural progenitors and stem cells cultivated from embryonic striatum. The increase of the number of GFAP-positive cells is associated with a significant decrease of the number of Tuj1- and O4-positive cells. Using quantitative RT-PCR, we demonstrate that mesenchymal stem cells express LIF, CNTF, BMP2 and BMP4 mRNAs, four cytokines known to play a role in astroglial fate decision. In this model, BMP4 is responsible for the astroglial stimulation and oligodendroglial inhibition, as 1) this cytokine is present in a biologically-active form only in nestin-positive mesenchymal stem cells conditioned medium and 2) anti-BMP4 antibodies inhibit the nestin-positive mesenchymal stem cells conditioned medium inducing effect on astrogliogenesis. CONCLUSIONS: When thinking carefully about mesenchymal stem cells as candidates for cellular therapy in neurological diseases, their effects on resident neural cell fate have to be considered

Exploring with [18F]UCB-H the in vivo cariations in SV2A expression through the kainic acid rat model of temporal lobe epilepsy

Purpose The main purpose of this study was to understand how the positron emission tomography (PET) measure of the synaptic vesicle 2A (SV2A) protein varies in vivo during the development of temporal lobe epilepsy (TLE) in the kainic acid rat model. Procedures Twenty Sprague Dawley male rats were administered with multiple systemic doses of saline (control group, n = 5) or kainic acid (5 mg/kg/injection, epileptic group, n = 15). Both groups were scanned at the four phases of TLE (early, latent, transition, and chronic phase) with the [F-18]UCB-H PET radiotracer and T2-structural magnetic resonance imaging. At the end of the scans (3 months post-status epilepticus), rats were monitored for 7 days with electroencephalography for the detection of spontaneous electrographic seizures. Finally, the immunofluorescence staining for SV2A expression was performed. Results Control rats presented a significant increase in [F-18]UCB-H binding at the last two scans, compared with the first ones (p < 0.001). This increase existed but was lower in epileptic animals, producing significant group differences in all the phases of the disease (p < 0.028). Furthermore, the quantification of the SV2A expression in vivo with the [F-18]UCB-H radiotracer or ex vivo with immunofluorescence led to equivalent results, with a positive correlation between both. Conclusions Even if further studies in humans are required, the ability to detect a progressive decrease in SV2A expression during the development of temporal lobe epilepsy supports the use of [F-18]UCB-H as a useful tool to differentiate, in vivo, between healthy and epileptic animals along with the development of the epileptic disease

Neuregulin signaling regulates neural precursor growth and the generation of oligodendrocytes in vitro

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