RESUMO
OBJECTIVE: Repair of demyelinated axons in diseases such as multiple sclerosis requires activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs). The control of OPC differentiation and initiation of myelination during repair is poorly understood. In this study, we test the ability of anti-LINGO-1 reagents to promote myelination in vitro and remyelination in the rodent adult central nervous system in vivo. METHODS: The effects of LINGO-1 antagonists on the differentiation of OPCs and the promotion of myelination has been assayed using a combination of coculture and slice culture preparations. Using three different animal models of demyelination and remyelination, we morphologically and functionally assessed the effects of LINGO-1 antagonists on OPC differentiation and myelin repair. RESULTS: The data indicate that in vitro treatment with antagonists of LINGO-1 promote OPC differentiation and myelination, whereas in vivo remyelination is accelerated in lysophosphatidylcholine- or cuprizone-induced demyelination. This remyelination is associated with enhanced OPC differentiation and functional recovery of conduction velocities in demyelinated axons. INTERPRETATION: Our studies demonstrate that LINGO-1 antagonism promotes OPC differentiation and remyelination, and suggest LINGO-1 functions as an inhibitor of OPC differentiation to retard central nervous system remyelination.
Assuntos
Diferenciação Celular/fisiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Oligodendroglia/fisiologia , Células-Tronco/fisiologia , Animais , Animais Recém-Nascidos , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Cuprizona/toxicidade , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/induzido quimicamente , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/tratamento farmacológico , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Gânglios Espinais/citologia , Lisofosfatidilcolinas/toxicidade , Proteínas de Membrana/imunologia , Proteínas de Membrana/fisiologia , Camundongos , Proteínas da Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/fisiologia , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacosRESUMO
Cyclosporine is one of the foremost immunosuppressive agents for cell, tissue, and organ transplantation. Cyclosporine is, however, associated with significant side effects in the host, and may also affect the fate of the donor cells. This study was performed to test whether cyclosporine may change the fate of neural stem cells, as neural stem cell transplant has become a potential treatment for neurological disorders and damage. Results of this study showed that cyclosporine inhibited the proliferation significantly in a dosage-dependent manner. Cyclosporine also affected the differentiation of neural stem cells, which mainly increased astrocyte genesis and decreased neuron differentiation.