Biomedical subjects

Monique Dubois-Dalcq

Publications and source records attributed to Monique Dubois-Dalcq.

8 recordsLinked to original sources

PubMed2006

Schwann cells genetically engineered to express PSA show enhanced migratory potential without impairment of their myelinating ability in vitro.

Schwann cells, the myelin-forming cells of the PNS, are attractive candidates for remyelination therapy as they can remyelinate CNS axons. Yet their integration in CNS tissue appears hampered, at least in part, by their limited motility in the CNS environment. As the polysialylated (PSA) form of NCAM regulates migration of neural precursors in the CNS and is not expressed by developing Schwann cells, we investigated whether conferring sustained expression of PSA to Schwann cells derived from postnatal rats enhances their motility. Cells were transduced with a retrovirus encoding polysialyl-transferase STX, an enzyme that synthesizes PSA on NCAM. Migration of wild type and transduced cells expressing STX or the marker gene alkaline phosphatase was examined using a gap bridging assay in dissociated cells and by grafting cells in slice cultures of postnatal brain. Migration of PSA expressing cells was significantly increased in both models, as compared to control cells, and this effect was abolished by endoneuraminidase-N stripping of PSA. PSA-positive Schwann cells retained the ability to differentiate in vitro and expressed the Krox20 and P zero myelination markers. When grafted in neonatal cerebellar slices, STX-transduced cells started to myelinate Purkinje cell axons like control cells and make myelin internodes after 2 to 3 weeks. PSA was redistributed on the cell membrane and downregulated during differentiation in pure Schwann cell cultures and slice co-cultures. Thus, migratory properties of PNS myelin-forming cells within the CNS can be enhanced without altering their differentiation program. This finding may be beneficial for the development of remyelination therapies.

Animals↗

PubMed2005

Enhancing central nervous system remyelination in multiple sclerosis.

Recent studies on adult neural stem cells and the developmental biology of myelination have generated the expectation that neural precursors can repair the damaged central nervous system of multiple sclerosis patients where the endogenous remyelination process has failed. As a result, many laboratories are engaged in translational studies in which the goal is to design ways to promote remyelination and repair. Here we raise issues highlighted by prior experimental and human work that should be considered lest these studies become "lost in translation."

Animals↗

PubMed2005

Effect of genetically modified Schwann cells with increased motility in end-to-side nerve grafting.

Taking into account that Schwann-cell (SC) motility is a prerequisite for myelination during peripheral nerve regeneration, the present study was designed with the intention to increase SC motility in vitro and to evaluate the effect of transduced SC on nerve regeneration in vivo, through silicone tubes after end-to-side nerve repair. Our in vitro study demonstrated that SC transduction with the pREV-HW3 retrovirus, encoding for sialyl-transferase-X (STX), significantly increased their motility compared to the control. In the in vivo study, 45 Wistar rats were randomized into three groups of 15 each. In all animals, the left peroneal nerve was severed, and a 10-mm segment was removed. The distal stump of the peroneal nerve was connected end-to-side to a perineurial window in the ipsilateral tibial nerve with either a silicone tube lined with SC (group A) or a silicone tube lined with STX-transduced SC (groups B and C). Fluorescence and light microscopy in group C showed that SCs were viable the first critical 15 postoperative days. After 90 days, light microscopy in group B demonstrated that STX-transduced SCs with increased motility ensured nerve regeneration, through silicone tubes, in all cases. Furthermore, STX-transduced SCs increased significantly fiber diameter and myelin thickness, and most importantly enhanced significantly the functional outcome compared to non-transduced SCs.

Animals↗

PubMed2004

Migrating and myelinating potential of neural precursors engineered to overexpress PSA-NCAM.

Polysialic acid (PSA) on NCAM is an important modulator of cell-cell interactions during development and regeneration. Here we investigated whether PSA overexpression influences neural cell migration and myelination. We stably expressed a GFP-tagged polysialytransferase, PSTGFP, in mouse neurospheres and induced prolonged PSA synthesis. Using a chick xenograft assay for migration, we show that PSA can instruct precursor migration along the ventral pathway. PSA persistence did not change neural precursor multipotentiality in vitro but induced a delay in oligodendrocyte differentiation. PSTGFP+ precursors showed widespread engraftment in shiverer brain, closely similar to that observed with control precursors expressing a fluorescent protein. Initially, myelination by oligodendrocytes was delayed but, eventually, down-regulation of PSTGFP occurred, allowing myelination to proceed. Thus down-regulation of polysialyltransferases takes place even in cells where its RNA is under the control of a heterologous promoter and engineering PSA overexpression in neural precursors does not cause irreversible unphysiological effects.

3T3 Cells↗

PubMed2003

Primordial hematopoietic stem cells generate microglia but not myelin-forming cells in a neural environment.

Finding ways to enhance remyelination is a major challenge in treating demyelinating diseases. Recent studies have suggested that circulating bone marrow cells can home in brain and transdifferentiate into neural cells. To ask whether hematopoietic precursors can form myelinating cells, we investigated the neuropoietic potential of embryonic precursors sorted from the mouse aorta-gonads-mesonephros (AGM) region. This cell fraction is capable of long-term hematopoietic reconstitution and generates colonies containing multipotential precursors and lymphoid or erythro-myeloid progenies. When cultured in hematopoietic growth conditions, a fraction of CD45-positive AGM cells coexpress neural markers such as nestin, the polysialylated form of neural cell adhesion molecule, the betaIII tubulin isoform, and glial fibrillary acidic protein. However, when hematopoietic precursors containing green fluorescent protein were cocultured with embryonic striatal precursors into neurospheres, they maintained their hematopoietic phenotype without undergoing differentiation into neurons, astrocytes, or oligodendrocytes. After intraventricular grafting, hematopoietic precursors integrated into the brain of wild-type or hypomyelinated newborn shiverer mice and gave rise to microglia but not neurons or glia. In contrast, when wild-type embryonic striatal neurospheres were grafted in shiverer, they formed numerous myelin internode patches. Even when neural and hematopoietic precursors were grafted together into shiverer mice, only neural precursors generated myelin-forming cells and synthesized myelin. Thus, embryonic neurospheres have myelin repair properties not shown by embryonic hematopoietic precursors. This suggests that the use of multipotential neural precursors to generate myelin-forming cells remains one of the most promising avenues toward remyelination therapies.

Animals↗

PubMed2003

CXCR4 regulates interneuron migration in the developing neocortex.

The chemotactic factors directing interneuron migration during cerebrocortical development are essentially unknown. Here we identify the CXC chemokine receptor 4 (CXCR4) in interneuron precursors migrating from the basal forebrain to the neocortex and demonstrate that stromal cell-derived factor-1 (SDF-1) is a potent chemoattractant for isolated striatal precursors. In addition, we show that CXCR4 is present in early generated Cajal-Retzius cells of the cortical marginal zone. In mice with a null mutation in CXCR4 or SDF-1, interneurons were severely underrepresented in the superficial layers and ectopically placed in the deep layers of the neocortex. In contrast, the submeningeal positioning of Cajal-Retzius cells was unaffected. Thus, our findings suggest that SDF-1, which is highly expressed in the embryonic leptomeninx, selectively regulates migration and layer-specific integration of CXCR4-expressing interneurons during neocortical development.

Animals↗

PubMed2003

Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system.

alpha-chemokines, which control the activation and directed migration of leukocytes, participate in the inflammatory processes in host defense response. One of the alpha-chemokines, CXCL12 or stromal cell-derived factor 1 (SDF-1), not only regulates cell growth and migration of hematopoietic stem cells but may also play a central role in brain development as we discuss here. SDF-1 indeed activates the CXCR4 receptor expressed in a variety of neural cells, and this signaling results in diverse biological effects. It enhances migration and proliferation of cerebellar granule cells, chemoattracts microglia, and stimulates cytokine production and glutamate release by astrocytes. Moreover, it elicits postsynaptic currents in Purkinje cells, triggers migration of cortical neuron progenitors, and produces pain by directly exciting nociceptive neurons. By modulating cell signaling and survival during neuroinflammation, SDF-1 may also play a role in the pathogenesis of brain tumors, experimental allergic encephalitis, and the nervous system dysfunction associated with acquired immunodeficiency syndrome.

Animals↗

PubMed2002

Sonic hedgehog is a potent inducer of rat oligodendrocyte development from cortical precursors in vitro.

Sonic Hedgehog (Shh) induces oligodendrocyte development in the ventral neural tube and telencephalon but its role in oligodendrocyte generation in dorsal telencephalon is debated. Transcripts for Shh and its receptor complex were detected in subventricular zone and neocortex from E17 to birth. As Shh is not yet expressed in E15 neocortex, we grew E15 cortical precursors (CP) into neurospheres in the presence of recombinant Octyl-Shh (O-Shh). After sphere adhesion and removal of O-Shh, enhanced neurite outgrowth and cell migration were already observed at 3 h. Three days after O-Shh treatment, oligodendrocyte progenitors (OP) emerged and continued to increase in number for 7 days while the ratio of neuronal cells decreased compared to control. Shh selectively triggered mitosis of OP but not neuronal progenitors and enhanced growth of neonatal OP. Thus Shh in E15-17 embryonic neocortex can signal CP to adopt an oligodendrocyte fate and favors expansion of this lineage.

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