Adult Bone Marrow Neural Crest Stem Cells and Mesenchymal Stem Cells are not able to Replace Lost Neurons in Acute MPTP-lesioned Mice

in PLoS ONE (in press)

Adult bone marrow stroma contains multipotent stem cells (BMSC) that are a mixed population of mesenchymal and neural-crest derived stem cells. Both cells are endowed with in vitro multi-lineage ... [more ▼]

Adult bone marrow stroma contains multipotent stem cells (BMSC) that are a mixed population of mesenchymal and neural-crest derived stem cells. Both cells are endowed with in vitro multi-lineage differentiation abilities, then constituting an attractive and easy-available source of material for cell therapy in neurological disorders. Whereas the in vivo integration and differentiation of BMSC in neurons into the central nervous system is currently matter of debate, we report here that once injected into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, pure populations of either bone marrow neural crest stem cells (NCSC) or mesenchymal stem cells (MSC) survived only transiently into the lesioned brain. Moreover, they do not migrate through the brain tissue, neither modify their initial phenotype, while no recovery of the dopaminergic system integrity was observed. Consequently, we tend to conclude that MSC/NCSC are not able to replace lost neurons in acute MPTP-lesioned dopaminergic system through a suitable integration and/or differentiation process. Altogether with recent data, it appears that neuroprotective, neurotrophic and anti-inflammatory features characterizing BMSC are of greater interest as regards CNS lesions management. [less ▲]

Neural fate of Mesenchymal Stem Cells and Neural Crest Stem Cells : Which ways to get neurons for cell therapy purpose ?

in Trends in cell signaling pathways in neuronal fate decision (2013)

Adult Bone Marrow Neural Crest and Mesenchymal Stem Cells : Which Role in Therapy of Neurological Pathologies ?

Poster (2013, January 28)

In Vivo Tumorigenesis Was Observed after Injection of In Vitro Expanded Neural Crest Stem Cells Isolated from Adult Bone Marrow

in PLoS ONE (2012), 7(10), 46425

Bone marrow stromal cells are adult multipotent cells that represent an attractive tool in cellular therapy strategies. Several studies have reported that in vitro passaging of mesenchymal stem cells ... [more ▼]

Bone marrow stromal cells are adult multipotent cells that represent an attractive tool in cellular therapy strategies. Several studies have reported that in vitro passaging of mesenchymal stem cells alters the functional and biological properties of those cells, leading to the accumulation of genetic aberrations. Recent studies described bone marrow stromal cells (BMSC) as mixed populations of cells including mesenchymal (MSC) and neural crest stem cells (NCSC). Here, we report the transformation of NCSC into tumorigenic cells, after in vitro long-term passaging. Indeed, the characterization of 6 neural crest-derived clones revealed the presence of one tumorigenic clone. Transcriptomic analyses of this clone highlighted, among others, numerous cell cycle checkpoint modifications and chromosome 11q down-regulation (suggesting a deletion of chromosome 11q) compared with the other clones. Moreover, unsupervised analysis such as a dendrogram generated after agglomerative hierarchical clustering comparing several transcriptomic data showed important similarities between the tumorigenic neural crest-derived clone and mammary tumor cell lines. Altogether, it appeared that NCSC isolated from adult bone marrow represents a potential danger for cellular therapy, and consequently, we recommend that phenotypic, functional and genetic assays should be performed on bone marrow mesenchymal and neural crest stem cells before in vivo use, to demonstrate whether their biological properties, after ex vivo expansion, remain suitable for clinical application. [less ▲]

Validation of Adult Bone Marrow Stromal Cells in Cellular Therapy Protocols, using a Mouse Model for Parkinson’s Disease

Poster (2012, May 04)

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in industrialized countries. Its main characteristic relies in a progressive loss of dopaminergic (DA) neurons in the ... [more ▼]

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in industrialized countries. Its main characteristic relies in a progressive loss of dopaminergic (DA) neurons in the Substantia Nigra pars compacta (SNpc), resulting in a deficient dopamine release in the striatum and then promoting important defects in motility regulation. Unfortunately, motor symptoms are generally diagnosed once 80% of nigrostriatal neurons are already lost. The emergence of neuroprotective/-restorative strategies is then increasingly raising hope, and a lot of people now focus on cell therapy experiments. Adult bone marrow stromal stem cells (BMSCs) have already been demonstrated as ideal candidates for cell therapy in nervous lesions, regarding their high multipotency and the fact they can be easily harvested in the patient himself. After it has been demonstrated that some BMSCs arise from the embryonic neural crest (NC), we compared NC-BMSCs and mesenchymal (M)-BMSCs in vitro, in terms of differenciation abilities and more particularly in terms of neural fate. We then wanted to investigate and compare the potential usefulness of both populations in the context of a neurological pathology. We have validated a MPTP mouse model, mimicking the specific loss of nigral neurons, and started setting up a cell therapy experiment using stereotaxic brain injection of the two types of BMSCs. The survival rate of grafted cells was analyzed as well as their migration or differentiation, and their ability to restore neuronal loss was also observed. Our first results showed that once grafted inside the brain of MPTP mice, NC-BMSCs survive for about a week, staying tightly close to each other the injection track with no visible sign of migration. Afterwards, cells begin to disappear and we only observe a mean survival rate of 1% after 28 days. Looking at the nigrostriatal pathway integrity, neural crest-BMSCs don’t seem to induce any improvement: they don’t differenciate into neural cells, neither replace lost DA cells, and they do not induce any sprouting of surviving DA neurons. While the M-BMSCs graft experiment has to be completed, these first results showed that NC-BMSCs at the stem cell state are not able to restore the lesioned system, and maybe a pre-differenciation step would be required to trigger those cells into a neuronal fate before grafting them in a MPTP-mouse brain. [less ▲]

Adult neural crest stem cells and neuronal fate decision

in Trends in cell signaling pathways in neuronal fate decision (2012)

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

in Molecular & Cellular Neuroscience [=MCN] (2010)

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 ... [more ▼]

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. [less ▲]

Cellular and Molecular Characterization of the neural phenotypic plasticity of the MSC.

Conference (2008)

Peripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression

in Biochemical Pharmacology (2005), 69(5), 819-830

Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising ... [more ▼]

Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising chemotherapeutic candidates. However, conflicting results were reported regarding the actual effect of these drugs on cellular survival ranging from protection to toxicity. Moreover, the concentrations needed to observe such a toxicity were usually high, far above the affinity range for their receptor, hence questioning its specificity. In the present study, we have shown that micromolar concentrations of FGIN-1-27 And Ro 5-4864, two chemically unrelated PBR ligands are toxic for both PBR-expressing SK-N-BE neuroblastoma cells and PBR-deficient Jurkat lymphoma cells. We have thereby demonstrated that the cytotoxicity of these drugs is unrelated to their PBR-binding activity. Moreover, Ro 54864-induced cell death differed strikingly between both cell types, being apoptotic in Jurkat cells while necrotic in SK-N-BE cells. Again, this did not seem to be related to PBR expression since Ro 5-4864-induced death of PBR-transfected Jurkat cells remained apoptotic. Taken together, our results show that PBR is unlikely to mediate all the effects of these PBR ligands. They however confirm that some of these ligands are very effective cytotoxic drugs towards various cancer cells, even for reputed chemoresistant tumors such as neuroblastoma, and, surprisingly, also for PBR-lacking tumor cells. (C) 2004 Elsevier Inc. All rights reserved. [less ▲]

Etude moléculaire et cellulaire des phénomènes de plasticité phénotypique nerveuse des cellules souches mésenchymateuses.

Conference (2002)