Le Bras, B. et al. VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain. Nature Neurosci. 9, 340-348

University of Helsinki, Helsinki, Uusimaa, Finland
Nature Neuroscience (Impact Factor: 16.1). 04/2006; 9(3):340-8. DOI: 10.1038/nn1646
Source: PubMed


Vascular endothelial growth factor C (VEGF-C) was first identified as a regulator of the vascular system, where it is required for the development of lymphatic vessels. Here we report actions of VEGF-C in the central nervous system. We detected the expression of the VEGF-C receptor VEGFR-3 in neural progenitor cells in Xenopus laevis and mouse embryos. In Xenopus tadpole VEGF-C knockdowns and in mice lacking Vegfc, the proliferation of neural progenitors expressing VEGFR-3 was severely reduced, in the absence of intracerebral blood vessel defects. In addition, Vegfc-deficient mouse embryos showed a selective loss of oligodendrocyte precursor cells (OPCs) in the embryonic optic nerve. In vitro, VEGF-C stimulated the proliferation of OPCs expressing VEGFR-3 and nestin-positive ventricular neural cells. VEGF-C thus has a new, evolutionary conserved function as a growth factor selectively required by neural progenitor cells expressing its receptor VEGFR-3.

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Available from: Barbara Le Bras
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    • "As previously reported [33,39,40], for chemotaxis and proliferation assays the cells were seeded in Bottenstein and Sato defined medium [41] consisting of DMEM with 1% FBS, 1% L-glutamine (Gibco), 0.03% BSA (Sigma), 1% antibiotic/antimycotic Solution (Sigma), 0.3 ng/ml 3,3´,5-triiodo-L-thyronine (T3, Sigma), 0.4 ng/ml thyroxine (Sigma), 16 µg/ml putrescine (Sigma), 40 ng/ml sodium selenite (Sigma), 9.3 µg/ml insulin (Sigma), 0.1 mg/ml holo-transferrin (Sigma) and 62 ng/ml progesterone (Sigma). "
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    ABSTRACT: During development, oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), a cell type that is a significant proportion of the total cells (3-8%) in the adult central nervous system (CNS) of both rodents and humans. Adult OPCs are responsible for the spontaneous remyelination that occurs in demyelinating diseases like Multiple Sclerosis (MS) and they constitute an interesting source of cells for regenerative therapy in such conditions. However, there is little data regarding the neurobiology of adult OPCs isolated from mice since an efficient method to isolate them has yet to be established. We have designed a protocol to obtain viable adult OPCs from the cerebral cortex of different mouse strains and we have compared its efficiency with other well-known methods. In addition, we show that this protocol is also useful to isolate functional OPCs from human brain biopsies. Using this method we can isolate primary cortical OPCs in sufficient quantities so as to be able to study their survival, maturation and function, and to facilitate an evaluation of their utility in myelin repair.
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    • "Additionally, they provided evidence that VEGF-C triggers a proliferative response in cultured optic nerve oligodendrocyte precursor cells. These results were corroborated by their observations with Vegfc +/− and Vegfcc −/− mouse embryos, both of which demonstrated reductions in the number of oligodendrocyte precursor cells compared to wild-type animals (Le Bras et al., 2006). The role of VEGF-C in the central nervous system is further expanded by Shin et al. (2008). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is usually fatal within 2-5 years. Unfortunately, the only treatment currently available is riluzole, which has limited efficacy. As a redress, there is an expanding literature focusing on other potential treatments. One such potential treatment option utilizes the vascular endothelial growth factor (VEGF) family, which includes factors that are primarily associated with angiogenesis but are now increasingly recognized to have neurotrophic effects. Reduced expression of a member of this family, VEGF-A, in mice results in neurodegeneration similar to that of ALS, while treatment of animal models of ALS with either VEGF-A gene therapy or VEGF-A protein has yielded positive therapeutic outcomes. These basic research findings raise the potential for a VEGF therapy to be translated to the clinic for the treatment of ALS. This review covers the VEGF family, its receptors and neurotrophic effects as well as VEGF therapy in animal models of ALS and advances towards clinical trials.
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    • "The expression of VEGFR-3 in subventricular zone suggests its participation in stem cell signaling. Even though, both VEGF-C and VEGF-D are ligands for VEGFR-3, VEGF-C inhibition severely reduces the proliferation of VEGFR-3 expressing neural progenitor cells in both xenopus tadpoles and in mice [55], indicating that VEGF-C: VEGFR-3 axis functions in the stem cell signaling in developing brain as well as in the pathophysiology of CNS diseases like stroke. Since, VEGF-C and VEGFR-3 signaling has been shown to modulate innate and adaptive immune responses in experimental obliterative bronchiolitis [56], we expect that this VEGF-C: VEGFR-3 axis might also play a key role in the pathophysiology of MS. "
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    ABSTRACT: Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin+ (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature. We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature.Results and conclusions: Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation.
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