Validation of Adult Bone Marrow Stromal Cells in Cellular Therapy Protocols, using a Mouse Model for Parkinson’s Disease
Neirinckx, Virginie ; ; Rogister, Bernard et al
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 ▲]Detailed reference viewed: 30 (5 ULg)
Altered balance between excitatory and inhibitory inputs onto CA1 pyramidal neurons from SV2A-deficient but not SV2B-deficient mice.
; Alix, Philippe ; et al
in Journal of Neuroscience Research (2012), 90(12), 2317-27
Synaptic vesicle protein 2 (SV2) is a glycoprotein that exists in three isoforms, SV2A, SV2B, and SV2C. SV2A knockout (KO) mice and SV2A/SV2B double KO (DKO) mice, but not SV2B KO animals, start to ... [more ▼]
Synaptic vesicle protein 2 (SV2) is a glycoprotein that exists in three isoforms, SV2A, SV2B, and SV2C. SV2A knockout (KO) mice and SV2A/SV2B double KO (DKO) mice, but not SV2B KO animals, start to experience severe seizures and weight loss 7 days after birth and die at about postnatal day (P)14-P23. Because excitatory and inhibitory inputs play a major role in controlling neuronal excitability in the hippocampus, we examined the effects of SV2A and/or SV2B deletions on glutamatergic and GABA(A) neurotransmission in hippocampal CA1 pyramidal neurons. Spontaneous and miniature excitatory and inhibitory postsynaptic currents (sEPSCs, mEPSCs, sIPSCs, and mIPSCs, respectively) were recorded using the whole-cell patch-clamp technique in slices from P6-P14 mice. The frequency of sEPSCs was increased in SV2A KO and SV2A/SV2B DKO mice, but their amplitude was unchanged. Such changes were not observed in SV2B KOs. On the contrary, the frequency and amplitude of sIPSCs were decreased in SV2A KO and SV2A/SV2B DKO mice but not in SV2B KO animals, as reported previously for the CA3 region. Kinetic parameters of sIPSCs and sEPSCs were unchanged. Importantly, no changes were observed in any genotype when examining mEPSCs and mIPSCs. We conclude that action potential- and Ca(2+) -dependent glutamatergic and GABAergic synaptic transmission are differentially altered in the hippocampus of SV2A-deficient mice, whereas the mechanism of exocytosis itself is not changed. The altered balance between these major excitatory and inhibitory inputs is probably a contributing factor to seizures in SV2A KO and SV2A/SV2B DKO mice. (c) 2012 Wiley Periodicals, Inc. [less ▲]Detailed reference viewed: 57 (0 ULg)
Adult neural crest stem cells and neuronal fate decision
Neirinckx, Virginie ; Rogister, Bernard ; Wislet, Sabine
in Trends in cell signaling pathways in neuronal fate decision (2012)Detailed reference viewed: 32 (4 ULg)
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.
Goffin, Eric ; ; et al
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 ▲]Detailed reference viewed: 83 (6 ULg)
Human muscle proteome modifications after acute or repeated eccentric exercises
Hody, Stéphanie ; Leprince, Pierre ; et al
in Medicine & Science in Sports & Exercise (2011), 43(12), 2281-2296
INTRODUCTION:: DOMS (Delayed-Onset Muscle Soreness), a condition triggered by eccentric exercise, affects muscle cells at a biochemical level in a poorly understood fashion. The objective of the present ... [more ▼]
INTRODUCTION:: DOMS (Delayed-Onset Muscle Soreness), a condition triggered by eccentric exercise, affects muscle cells at a biochemical level in a poorly understood fashion. The objective of the present study was to examine human muscle proteome modifications induced by strenuous eccentric exercises following a specific training aimed to prevent DOMS. METHODS:: Biopsy of the rectus femoris were taken from healthy human volunteers in three successive conditions: (1) at rest, (2) 24 hours after an injuring exercise protocol consisting of 3 series of 30 maximal contractions of the quadriceps on an isokinetic dynamometer, (3) 24 hours after a similar exercise bout preceded either by 5 eccentric training sessions, or no training. RESULTS:: Muscle damage was assessed before and 1 day after each maximal eccentric test by comparing three indirect markers: plasma activity of creatine kinase (CK), muscle stiffness and subjective pain intensity. Compared to the first eccentric test, those markers were reduced after the second test and further reduced if this second test followed the eccentric training, thus confirming the protective effect of such training. Muscle protein extracts were subjected to a 2D-DIGE proteomic analysis coupled with MALDI-TOF-MS protein identification. Surprisingly, we observed that myosin heavy chains decreased after the first eccentric test, and were reduced further with other contractile proteins after the second test. Furthermore, the expression of several glycolytic enzymes decreased only after the second test that was preceded by a specific training. CONCLUSION:: These findings suggest that the eccentric training resulted in a switch to oxidative metabolism, which may be associated with protection from DOMS. [less ▲]Detailed reference viewed: 124 (37 ULg)
Adult bone marrow: which stem cells for cellular therapy protocols in neurodegenerative disorders?
Wislet-Gendebien, Sabine ; Laudet, Emerence ; Neirinckx, Virginie et al
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 ▲]Detailed reference viewed: 55 (15 ULg)
Wnt1 and BMP2: two factors recruiting multipotent neural crest progenitors isolated from adult bone marrow
Glejzer, Aneta ; Laudet, Emerence ; Leprince, Pierre et al
in Cellular and Molecular Life Sciences : CMLS (2011), 68/12
Recent studies have shown that neural crestderived progenitor cells can be found in diverse mammalian tissues including tissues that were not previously shown to contain neural crest derivatives, such as ... [more ▼]
Recent studies have shown that neural crestderived progenitor cells can be found in diverse mammalian tissues including tissues that were not previously shown to contain neural crest derivatives, such as bone marrow. The identification of those ‘‘new’’ neural crest-derived progenitor cells opens new strategies for developing autologous cell replacement therapies in regenerative medicine. However, their potential use is still a challenge as only few neural crest-derived progenitor cells were found in those new accessible locations. In this study, we developed a protocol, based on wnt1 and BMP2 effects, to enrich neural crest-derived cells from adult bone marrow. Those two factors are known to maintain and stimulate the proliferation of embryonic neural crest stem cells, however, their effects have never been characterized on neural crest cells isolated from adult tissues. Using multiple strategies from microarray to 2D-DIGE proteomic analyses, we characterized those recruited neural crest-derived cells, defining their identity and their differentiating abilities. [less ▲]Detailed reference viewed: 110 (35 ULg)
Human glioblastoma-initiating cells invade specifically the subventricular zones and olfactory bulbs of mice after striatal injection.
Kroonen, Jérôme ; Nassen, Jessica ; et al
in International Journal of Cancer = Journal International du Cancer (2011), 129(3), 574-585
This study reports the subsequent isolation of human glioblatoma cells able to initiate experimental brain tumors, specifically and repeatedly found in the subventricular zones and olfactory bulbs ... [more ▼]
This study reports the subsequent isolation of human glioblatoma cells able to initiate experimental brain tumors, specifically and repeatedly found in the subventricular zones and olfactory bulbs following xenograft in the caudate putamen of immunodeficient mice.In patients with glioblastoma multiforme, recurrence is the rule despite continuous advances in surgery, radiotherapy and chemotherapy. Within these malignant gliomas, glioblastoma stem cells or initiating cells have been recently described and they were shown to be specifically involved in experimental tumorigenesis. In this study, we show that some human glioblastoma cells injected into the striatum of immunodeficient nude mice exhibit a tropism for the subventricular zones. There and similarily to neurogenic stem cells, these subventricular glioblastoma cells were then able to migrate towards the olfactory bulbs. Finally, the glioblastoma cells isolated from the adult mouse subventricular zones and olfactory bulbs display high tumorigenicity when secondary injected in a new mouse brain. Together, these data suggest that neurogenic zones could be a reservoir for particular cancer-initiating cells. [less ▲]Detailed reference viewed: 84 (35 ULg)
Neural crest stem cells from adult bone marrow: a new source for cell replacement therapy?
; Neirinckx, Virginie ; Rogister, Bernard et al
in Wislet, Sabine (Ed.) Advance in Regenerative Medicine (2011)Detailed reference viewed: 117 (7 ULg)
Delayed-Onset Muscle Soreness and its prevention in humans: a proteomic analysis unravels modifications of glycolytic enzymes and contractile proteins expression
Hody, Stéphanie ; Leprince, Pierre ; Croisier, Jean-Louis et al
Conference (2010, April 24)Detailed reference viewed: 54 (6 ULg)
Neuregulin-1 modulates the differentiation of neural stem cells in vitro trough an interaction with the Swi/Snf complex.
Pirotte, Dorothée ; Wislet, Sabine ; et al
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 ▲]Detailed reference viewed: 144 (10 ULg)
Proteomic comparison of High and Low responders to eccentric exercise
Hody, Stéphanie ; Croisier, Jean-Louis ; Leprince, Pierre et al
in Abstract book du Colloque de la Société Belge des Neurosciences (2009, May)Detailed reference viewed: 32 (11 ULg)
Courbatures après exercice excentrique : High et Low responders ?
Hody, Stéphanie ; Rogister, Bernard ; Croisier, Jean-Louis et al
in Croisier, Jean-Louis; Codine, Philippe (Eds.) Exercice musculaire excentrique (2009)
It is well known that novel and/or unusual exercise consisting of lengthening muscle contractions (eccentric exercise) results in muscle damage. Muscle damage can be assessed via measures of indirect ... [more ▼]
It is well known that novel and/or unusual exercise consisting of lengthening muscle contractions (eccentric exercise) results in muscle damage. Muscle damage can be assessed via measures of indirect markers such as isometric strength, range of motion, blood levels of muscle-specific proteins and muscle soreness. It has been shown that changes in these markers present a large inter-subject variability. Especially, the seric CK response to exercise is largely documented and some authors introduced the notion of High and Low responders to define subjects with exaggerated and light or moderate response to eccentric protocol, respectively. The reasons for the various susceptibility to eccentric exercise are not understood but it seems to be influenced by several factors including genetical, morphological, physiological or training elements. Further studies are necessary to elucidate the underlying mechanisms of the large inter-subject variability in responses to eccentric exercise and in this context, a proteomic approach could be interesting to highlight protein expression differences between High and Low responders. [less ▲]Detailed reference viewed: 195 (53 ULg)
DOMS : traiter ou prévenir ?
Hody, Stéphanie ; Rogister, Bernard ; Leprince, Pierre et al
in Croisier, Jean-Louis; Codine, Philippe (Eds.) Exercice musculaire excentrique (2009)
The evidence of benefits from eccentric contraction provides compelling rationale for their inclusion in force training and in the reeducation of various locomotor pathologies (i.e., tendinopathies or ... [more ▼]
The evidence of benefits from eccentric contraction provides compelling rationale for their inclusion in force training and in the reeducation of various locomotor pathologies (i.e., tendinopathies or muscular imbalance). However, intense or unusual eccentric exercise frequently leads to muscle damage associated with prolonged loss in muscle strength and range of motion, a dramatic increase in muscle proteins circulating in blood and the development of muscle soreness. These negative functional consequences, referred to as Delayed Onset Muscle Soreness (DOMS), often disturb the progress of training or reeducation programmes. In an attempt to attenuate signs and symptoms of DOMS, several approaches have been used prophylactically and/or therapeutically. This article focuses on some of the most commonly used modalities, including the nutritionnal and pharmacological strategies, clinical therapies and exercise. Despite a large number of studies, there is little evidence indicating any benefit at the perfomance level of these various approaches. Conversely, there is unequivocal evidence that a bout of eccentric exercise is followed by protection against skeletal muscle damage associated with a subsequent bout of potentially damaging exercise for several weeks to several months. To date, specific submaximal training appears the most efficient prophylactic measure and is recommended to alleviate the prejudiciable consequences associated with DOMS in the athletic or therapeutic programs. Despite the volume of data concerning this protective effect, often called the “repeated bout effect”, the underlying mechanisms of such an adaptation are not fully understood and a better knowledge of these adaptative mechanisms could provide better guidelines for prevention or treatment practice. [less ▲]Detailed reference viewed: 197 (47 ULg)
La neurogenese adulte ou l'histoire d'un dogme qui s'ecroule.
Pirotte, Dorothée ; Rogister, Bernard
in Revue Médicale de Liège (2008), 63(5-6), 245-50
The history of sciences is characterized by major discoveries, but also by challenges of theories or dogma previously established and accepted by everybody. One of the recent examples illustrating such a ... [more ▼]
The history of sciences is characterized by major discoveries, but also by challenges of theories or dogma previously established and accepted by everybody. One of the recent examples illustrating such a questioning relates to the demonstration of the persistence of a cerebral neurogenesis in the adult brain, including in human. This adult neurogenesis is however limited, both in space (it concerns only the subventricular zone and the gyrus dentatus in the hippocampus) and the type of newly-formed neurons (interneurones which most of them are GABAergic and present respectively in the olfactive bulb and CA1 area of the hippocampus). Moreover, this neurogenesis does not seem to be recruited after a brain lesion, a situation which explains why functional recovery when it is observed remains a consequence of brain plasticity. We thus legitimately address the question about the physiological role of this adult brain neurogenesis as well as a possible implication in the aetiology of various neurological disorders, like the neurodegenerative diseases or epilepsy, but also in psychiatric diseases like depression. [less ▲]Detailed reference viewed: 830 (22 ULg)
Les glioblastomes, un exemple de recherche translationnelle?
Kroonen, Jérôme ; Nguyen-Khac, Minh-Tuan ; Deprez, Manuel et al
in Revue Médicale de Liège (2008), 63(5-6), 251-6
Among patients which develop glioblastoma multiform (GBM), recurrence is the rule despite continuous progress in surgery, radiotherapy and chemotherapy. In the adult, GBM is the most frequent and most ... [more ▼]
Among patients which develop glioblastoma multiform (GBM), recurrence is the rule despite continuous progress in surgery, radiotherapy and chemotherapy. In the adult, GBM is the most frequent and most aggressive tumour of the Central Nervous System. A better understanding of the mechanisms by which these tumours relapse could promote the use of preventive therapy and could increase patients' survival. GBM stem cells have been recently described and it was demonstrated that they are specifically implied in the experimental tumorigenesis. It is thus very attractive to speculate on a possible relationship between these GBM stem cells and the neural stem cells which are persisting in the neurogenic zones of the adult brain. In this review, we formulate and discuss the hypothesis by which, in a patient with GBM, malignant stem cells might be present in the neurogenic zones, away from the tumour mass. This hypothesis could explain the tumour relapse observed after the first treatments. [less ▲]Detailed reference viewed: 170 (51 ULg)
Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease.
; ; et al
in Molecular & Cellular Neuroscience [=MCN] (2008), 37(3), 454-70
Neural and mesenchymal stem cells have been proposed as alternative sources of cells for transplantation into the brain in neurodegenerative disorders. However, the endogenous factors controlling their ... [more ▼]
Neural and mesenchymal stem cells have been proposed as alternative sources of cells for transplantation into the brain in neurodegenerative disorders. However, the endogenous factors controlling their engraftment within the injured parenchyma remain ill-defined. Here, we demonstrate significant engraftment of undifferentiated exogenous mesenchymal or neural stem cells throughout the lesioned area in a rat model for Huntington's disease, as late as 8 weeks post-transplantation. We show that stem cell factor (SCF), strongly up-regulated within host cells in the damaged striatum, is able to activate the SCF receptor c-kit and its signaling pathway and to promote the migration and proliferation of mesenchymal and neural stem cells in vitro. Furthermore, c-kit receptor blockade alters neural stem cell distribution within the lesioned striatum. Host SCF expression is observed in atypical cells expressing glial fibrillary acidic protein and doublecortin in the lesioned striatum and in migrating doublecortin-positive progenitors. Taken together, these data demonstrate that SCF produced in situ in the lesioned striatum is an important factor in promoting the engraftment of stem cells within the lesioned brain. [less ▲]Detailed reference viewed: 126 (7 ULg)
Interest of a comparative proteomic approach to unravel the aetiology of DOMS in humans
Hody, Stéphanie ; Croisier, Jean-Louis ; Wang, François-Charles et al
in Acta Physiologica Scandinavica. Supplementum (2008), 194(suppl 666), -09Detailed reference viewed: 50 (20 ULg)
Does neural phenotypic plasticity from non-neural cells really exist?
Wislet, Sabine ; ; Laudet, Emerence et al
in Ivanova, laura (Ed.) Cell differentiation Research Developments (2008)Detailed reference viewed: 36 (7 ULg)
Cellular and Molecular Characterization of the neural phenotypic plasticity of the MSC.
Wislet, Sabine ; Rogister, Bernard
Conference (2008)Detailed reference viewed: 7 (0 ULg)