Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models

Failure of remyelination of multiple sclerosis (MS) lesions contributes to neurodegeneration that correlates with chronic disability in patients. Currently, there are no available treatments to reduce neurodegeneration, but one therapeutic approach to fill this unmet need is to promote remyelination. As many demyelinated MS lesions contain plentiful oligodendrocyte precursor cells (OPCs), but no mature myelinating oligodendrocytes, research has previously concentrated on promoting OPC maturation. However, some MS lesions contain few OPCs, and therefore, remyelination failure may also be secondary to OPC recruitment failure. Here, in a series of MS samples, we determined how many lesions contained few OPCs, and correlated this to pathological subtype and expression of the chemotactic molecules Semaphorin (Sema) 3A and 3F. 37 % of MS lesions contained low numbers of OPCs, and these were mostly chronic active lesions, in which cells expressed Sema3A (chemorepellent). To test the hypothesis that differential Sema3 expression in demyelinated lesions alters OPC recruitment and the efficiency of subsequent remyelination, we used a focal myelinotoxic mouse model of demyelination. Adding recombinant (r)Sema3A (chemorepellent) to demyelinated lesions reduced OPC recruitment and remyelination, whereas the addition of rSema3F (chemoattractant), or use of transgenic mice with reduced Sema3A expression increased OPC recruitment and remyelination. We conclude that some MS lesions fail to remyelinate secondary to reduced OPC recruitment, and that chemotactic molecules are involved in the mechanism, providing a new group of drug targets to improve remyelination, with a specific target in the Sema3A receptor neuropilin-1. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-013-1112-y) contains supplementary material, which is available to authorized users

Interleukin-6, interferon-gamma, interleukin-8, and granulocyte-macrophage colony stimulating factor levels in human amniotic fluid at term

Cytokines contribute to the maintenance of successful pregnancy and have also been implicated in the initiation of labour. This study has examined those cytokines which may be involved in normal term parturition. IL-6, IFN-gamma, IL-8 and GM-CSF levels were measured by ELISA in samples of amniotic fluid, peripheral and uterine venous blood plasma, and umbilical artery blood plasma from non-labouring women undergoing elective caesarean section at term and from women in spontaneous labour. IFN-gamma and IL-6 were detected only in amniotic fluid and not in blood plasma samples, unlike IL-8 which was found in all amniotic fluid and plasma samples from both labouring and non-labouring women; GM-CSF was undetectable in all samples examined. Levels of IL-6 were significantly raised in the amniotic fluid of women in labour compared with the control group (P = 0.008). IFN-gamma was detected in the amniotic fluid of both labouring women and the control group, and there was also a significant correlation (P = 0.003) between IFN-gamma and IL-6 levels in individual amniotic fluid samples. The presence of both IFN-gamma and IL-8 in amniotic fluid, as well as IL-6, suggests these cytokines are involved in important immunobiological events relevant to the latter half of gestation