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 ▲]

Effects of eccentrically and concentrically biased training on mouse muscle phenotype

in Medicine & Science in Sports & Exercise (2013)

Introduction: The molecular adaptations specifically induced by different muscle contraction types have only been partially elucidated. We previously demonstrated that eccentric contractions in human ... [more ▼]

Introduction: The molecular adaptations specifically induced by different muscle contraction types have only been partially elucidated. We previously demonstrated that eccentric contractions in human quadriceps elicited proteome modifications that suggest a muscle fiber typology adaptation. We address this question in a more systematic way by examining here the effects of different running modes on the mouse muscle proteome and the muscle fiber typology. Methods: Male adult mice (C57BL6) were randomly divided into downhill running (DHR, quadricipital eccentrically biased contractions), uphill running (UHR, quadricipital concentrically biased contractions) and untrained control (CONT) groups. Running groups performed five training sessions on an inclined treadmill for 75 to 135 min/day and the quadriceps muscles were dissected 96hours after the last session. Muscle protein extracts of DHR and UHR groups (n=4/group) were subjected to a 2D-DIGE analysis coupled with mass spectrometry. The assessment of fiber type, size and number was performed on the rectus femoris of the three groups (n=6/group) using myosin heavy chain (MHC) immunohistochemistry. Results: In the proteomic analysis, eight spots identified as the fast MHC isoforms exhibited a lower abundance in DHR compared to UHR (p<0.05, t-test). In contrast, ATP synthase subunit α and tubulin β were more expressed in DHR (p<0.05). A significant higher proportion of type I and IIa fibers was found for DHR compared to UHR or CONT groups (p<0.05, one-way ANOVA). Conclusions: Our data suggest that the eccentrically biased contractions in mice induced specific adaptations in protein expression and muscle fiber composition which may reflect a more oxidative muscle phenotype. The differences in stress placed on the muscle between both trainings may be responsible for some unique adaptations resulting from the eccentrically biased training. [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)

In vitro and in vivo Characterization of Adult Bone Marrow Neural Crest Stem Cells and their Implication in Hematopoietic Support

Poster (2013, January 28)

The susceptibility of the knee extensors to eccentric exercise-induced muscle damage is not affected by leg dominance but by exercise order .

in Clinical Physiology & Functional Imaging (2013)

The aims of this study were first to compare the response of dominant and non-dominant legs to eccentric exercise and second, to examine whether there is an effect of exercise order on the magnitude of ... [more ▼]

The aims of this study were first to compare the response of dominant and non-dominant legs to eccentric exercise and second, to examine whether there is an effect of exercise order on the magnitude of symptoms associated with intense eccentric protocols. Eighteen young men performed 3 sets of 30 maximal eccentric isokinetic (60°.sec-1) contractions of the knee extensors (range of motion, ROM: 0°-100°, 0=full extension) using either dominant or nondominant leg. They repeated a similar eccentric bout using the contralateral leg six weeks later. The sequence of leg’s use was allocated to create equally balanced groups. Four indirect markers of muscle damage including subjective pain intensity, maximal isometric strength, muscle stiffness and plasma CK activity were measured before and 24 hours after exercise. All markers changed significantly following the eccentric bout performed either by dominant or non-dominant legs but no significant difference was observed between legs. Interestingly, the comparison between the first and second eccentric bouts revealed that muscle soreness (-42%, p<0.001), CK activity (-62%, p<0.05) and strength loss (-54%, p<0.01) were significantly lower after the second bout. This study suggests that leg dominance does not influence the magnitude of exercise-induced muscle damage and supports for the first time the existence of a contralateral protection against exercise-induced muscle damage in the lower limbs. [less ▲]

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 ▲]

Proteomic comparison of high and low responders to eccentric exercise

in Meeusen, R.; Duchateau, J.; Roelands, B. (Eds.) et al Book of Abstracts of the 17th annual Congress of the ECSS (2012, July)

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 ▲]

N-Aryl-N'-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: screening, synthesis of simplified derivatives, and structure-activity relationship analysis.

in European Journal of Medicinal Chemistry (2012), 54

A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three ... [more ▼]

A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three human high-grade glioma cell lines: U373, T98G, and Hs683. Significant in vitro growth inhibitory activity was observed with 2,2-dimethylchroman-type nitro-substituted phenylthioureas, such as compounds 4o and 4p. Interestingly, most tested phenylureas were found to be slightly less active, but more cell selective (normal versus tumor glial cells, such as 3d, 3e, and 3g), thus less toxic, than the corresponding phenylthioureas. No significant differences were observed in terms of chroman-derivative-induced growth inhibitory effects between glioma cells sensitive to pro-apoptotic stimuli (Hs683 glioma cells) and glioma cells associated with various levels of resistance to pro-apoptotic stimuli (U373 and T98G glioma cells), a feature that suggests non-apoptotic-mediated growth inhibition. Flow cytometry analyses confirmed the absence of pro-apoptotic effects for phenylthioureas and phenylureas when analyzed in U373 glioma cells and demonstrated U373 cell cycle arrest in the G0/G1 phase. Computer-assisted phase-contrast videomicroscopy revealed that 3d and 3g displayed cytostatic effects, while 3e displayed cytotoxic ones. As a result, this work identified phenylurea-type 2,2-dimethylchromans as a new class of antitumor agents to be further explored for an innovative therapeutic approach for high-grade glioma and/or for a possible new mechanism of action. [less ▲]

Adult bone marrow: which stem cells for cellular therapy protocols in neurodegenerative disorders?

in Journal of Biomedicine & Biotechnology (2011)

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 ... [more ▼]

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 (NCSC) 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 (MSC). In this manuscript, we will review all information available concerning NCSC from adult tissues and their possible use in regenerative medecine. 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. [less ▲]