ABSTRACT
Oligodendrocyte maturation is necessary for functional regeneration in the CNS; however, the mechanisms by which the systemic environment regulates oligodendrocyte maturation is unclear. We found that Transforming growth factor (TGF)-ß1, which is present in higher levels in the systemic environment, promotes oligodendrocyte maturation. Oligodendrocyte maturation was enhanced by adult mouse serum treatment via TGF-ß type I receptor. Decrease in circulating TGF-ß1 level prevented remyelination in the spinal cord after toxin-induced demyelination. TGF-ß1 administration promoted remyelination and restored neurological function in a multiple sclerosis animal model. Furthermore, TGF-ß1 treatment stimulated human oligodendrocyte maturation. These data provide the therapeutic possibility of TGF-ß for demyelinating diseases.
Subject(s)
Central Nervous System/drug effects , Demyelinating Diseases/drug therapy , Multiple Sclerosis/drug therapy , Oligodendroglia/drug effects , Remyelination/drug effects , Transforming Growth Factor beta1/administration & dosage , Adult , Animals , Cells, Cultured , Demyelinating Diseases/chemically induced , Disease Models, Animal , Humans , Mice , Transforming Growth Factor beta1/blood , Treatment OutcomeABSTRACT
Angiogenesis, a prominent feature of pathology, is known to be guided by factors secreted by living cells around a lesion. Although many cells are disrupted in a response to injury, the relevance of degenerating cells in pathological angiogenesis is unclear. Here, we show that the release of lactate dehydrogenase A (LDHA) from degenerating neurons drives central nervous system (CNS) angiogenesis. Silencing neuronal LDHA expression suppressed angiogenesis around experimental autoimmune encephalomyelitis (EAE)- and controlled cortical impact-induced lesions. Extracellular LDHA-mediated angiogenesis was dependent on surface vimentin expression and vascular endothelial growth factor receptor (VEGFR) phosphorylation in vascular endothelial cells. Silencing vimentin expression in vascular endothelial cells prevented angiogenesis around EAE lesions and improved survival in a mouse model of glioblastoma. These results elucidate novel mechanisms that may mediate pathologic angiogenesis and identify a potential molecular target for the treatment of CNS diseases involving angiogenesis.
Subject(s)
Central Nervous System/blood supply , Central Nervous System/pathology , Extracellular Space/enzymology , L-Lactate Dehydrogenase/metabolism , Neovascularization, Pathologic/enzymology , Neurons/enzymology , Neurons/pathology , Animals , Axons/pathology , Cell Membrane/metabolism , Cell Proliferation , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/enzymology , Encephalomyelitis, Autoimmune, Experimental/pathology , Endothelial Cells/enzymology , Glioblastoma/pathology , Isoenzymes/metabolism , Lactate Dehydrogenase 5 , Mice, Inbred C57BL , Nerve Degeneration/pathology , Nerve Regeneration , Protein Binding , Survival Analysis , Vascular Endothelial Growth Factor Receptor-2/metabolism , Vimentin/metabolismABSTRACT
Demyelination in the central nervous system (CNS) leads to severe neurological deficits that can be partially reversed by spontaneous remyelination. Because the CNS is isolated from the peripheral milieu by the blood-brain barrier, remyelination is thought to be controlled by the CNS microenvironment. However, in this work we found that factors derived from peripheral tissue leak into the CNS after injury and promote remyelination in a murine model of toxin-induced demyelination. Mechanistically, leakage of circulating fibroblast growth factor 21 (FGF21), which is predominantly expressed by the pancreas, drives proliferation of oligodendrocyte precursor cells (OPCs) through interactions with ß-klotho, an essential coreceptor of FGF21. We further confirmed that human OPCs expressed ß-klotho and proliferated in response to FGF21 in vitro. Vascular barrier disruption is a common feature of many CNS disorders; thus, our findings reveal a potentially important role for the peripheral milieu in promoting CNS regeneration.
