Biomedical Engineering Reference
In-Depth Information
attacks to the neural tissue and an overall failure of the remyelination process driven
by endogenous oligodendrocyte precursor cells (OPCs) undergoing activation upon
myelin damage [
16
]. Immune modulation and remyelination are, therefore, the main
aims of the newest therapeutic interventions for MS [
17
,
18
].
Most of the licensed drug therapies focus their mechanism of action at the
suppression of the immune response, as the induction of remyelination is partic-
ularly complicated because of the disseminated (in space and time) and recurrent
nature of MS [
19
]. There is currently no treatment for the motor, sensory, and
cognitive deficits of chronic, late stage, progressive MS cases [
17
,
18
]. Hence,
stem cells might represent a potentially valuable therapeutic option for MS
patients in their progressive stages, based on their tissue trophic (e.g., neurore-
generative), and immune regulatory potential. A wide range of transplantation
studies using NPCs have been performed in mice with both chronic and relapsing
EAE, the prototypical animal model for MS.
As consequence of these studies, solid evidence has been provided that the
systemic (either intravenous or intracerebroventricular) transplantation of NPCs
into EAE rodents reduces the amount of astrogliosis, demyelination, and axonal
loss without overt side effects [
20
-
24
]. Accumulation of systemically injected
NPCs into inflamed CNS areas in EAE is shown to be dependent from the con-
stitutive expression of functional adhesion molecules (e.g., CD44), integrins (e.g.,
a4, b1), and chemokine receptors (e.g., CCR1, CCR2, CCR5, CXCR3, CXCR4)
[
21
,
25
](pathotropism). This adhesion molecule/chemokine receptor-dependent
pathotropism of NPCs is well conserved across species, and has been recently
confirmed also on human NPCs [
26
-
28
] that have ameliorated the clinic-patho-
logical features of EAE nonhuman primates, after systemic NPC injection [
27
].
Remarkably, the functional recovery observed after NPC transplantation—both
in rodents and nonhuman primates—has always scarcely correlated with the
absolute numbers of derived terminally differentiated neural cells in vivo, thus
suggesting a mechanism of action clearly distinct from the initially prospected
replacement of damaged endogenous neural cells [
12
]. As such, NPCs accumu-
lating and surviving at the level of the CNS inflammatory areas exert a number of
tissue trophis and immune modulatory effects, and in turn decrease CNS inflam-
mation and prevent the accumulation of secondary tissue damage [
8
].
NPCs may enhance intrinsic endogenous repair mechanisms e.g., by exerting
neurotrophic activities that increase the number of OPCs recruited at the lesion level.
As such, systemically injected NPCs in EAE mice increase the number of endoge-
nous OPCs at the lesion site, thus improving spontaneous remyelination [
21
].
This effect on OPCs is paralleled by a decrease of the pro (astro)gliotic factors
transforming growth factor (TGF)-b and fibroblast growth factor (FGF)-2 [
21
].
In cuprizone-induced demyelination, intracerebroventricularly transplanted NPCs
induced OPC proliferation and enhanced remyelination via the secretion of the
platelet-derived growth factor (PDGF)-AA and FGF-2 [
29
]. NPCs also secrete
leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF); while the
former promotes mature oligodendrocyte survival in EAE [
30
,
31
], the latter has been
implicated in both OPC survival and differentiation [
32
,
33
].
