| dc.description.abstract | Multiple Sclerosis (MS) is an inflammatory disease which causes areas of demyelination in
the Central Nervous System (CNS) and affects only humans. Current therapies for MS are
focused on anti-inflammatory treatment, which reduce the occurrence and clinical relapses of
the disease. However, progressive disability of the disease is related to axonal degeneration.
After demyelination, remyelination occurs, which helps repair the demyelinated lesions and
protects axons from degeneration. However, this endogenous remyelination is inefficient,
and currently there are no therapies available to enhance remyelination.
The aim of this
thesis was to first characterize a fast and reliable model to study CNS remyelination in vitro,
and second to investigate the role of semaphorin 3a (Sema3A) and semaphorin 3f (Sema3F)
signaling in CNS remyelination.
Various in vivo models have been developed to investigate the pathology of multiple
sclerosis, and can be used to test remyelination therapies. However, in vivo models are
expensive, animal- and time- consuming. Until now, there has been no well-characterized
and robust in vitro model for remyelination study. In this thesis, an ex vivo slice culture
system with mouse brain and spinal cord was developed, and characterized by
immunofluorescent microscopy and transmission electron microscopy, for CNS
remyelination study. Automated (re)myelinating quantification by image pro plus software
was developed and validated to provide a fast and reliable way for testing factors that change
remyelination efficiency.
Two such factors are Sema3A and 3F, which were initially identified as axon guidance cues
during development. Sema3A (repulsive) and 3F (attractive) were proved to play a role in
oligodendrocyte precursor cell (OPC) migration during development, and hypothesized to be
important in remyelination. In this thesis, I investigated the effects and mechanisms for this
by adding recombinant SEMA3A or SEMA3F or by knockdown their obligatory receptors
Neuropilin (Nrp) 1 and 2, using lentivirus induced miRNAi. Slice culture and primary OPC
culture were used to determine the effect on OPC survival, migration, proliferation,
differentiation and myelination. | en |
