Biomedical Engineering Reference
In-Depth Information
In summary, NPCs have been shown to exert not only trophic support at the
EAE lesioned CNS microenvironment, but also to play a crucial role at peripheral
lymphoid organs in the regulation of the immune responses to myelin antigens
[
42
-
44
].
2.3 Brain Stroke
Stroke and other cerebrovascular diseases are the second leading cause of death in
middle and high-income countries. Stroke attacks are mostly caused by thrombosis
or embolism, while hemorrhagic strokes are less frequent. Patients can suffer form
paralysis, spasticity, aphasia, or dementia, disabilities that have a significant
impact on their quality of life [
45
]. Clinical recovery after stroke remains very
poor despite advances in therapy, and stem cell treatments are greatly considered
as a promising alternative [
46
]. Transplantation of NPCs with different delivery
strategies, intraparenchymal, or intracerebroventricular injection, as well as sys-
temic administration, has been shown to improve clinical signs in experimental
stroke models [
47
,
48
].
When injected into the ischemic brain, NPCs tend to migrate towards the
infarct sit [
49
-
52
], where chemoattractive gradients of proinflammatory cytokines
and chemokines are released [
53
], and a crucial role of CCL2/CCR2 and CXCL12/
CXCR4 in transendothelial recruitment and intraparenchymal migration, respec-
tively [
54
-
56
], is established. Once they reach the boundaries of the ischemic area,
grafted NPCs are shown to interact with the inflammatory environment, as sug-
gested by the increase in the gene expression levels of VEGF, CXCL12/SDF1-a,
and TGF-b in the NPC-transplanted mouse middle cerebral artery (MCA) occlu-
sion brain at 4 h after the insult [
57
]. Intracerebrally transplanted NPCs are able to
differentiate into neurons and glia. NPC-derived neurons have been described to
produce neurotransmitters, form dendrites and show electrophysiological proper-
ties characteristics of integrated functional neurons [
58
-
60
]. However, only a
minor percentage of transplanted NPCs undergo terminal differentiation or mainly
differentiate towards a glial phenotype [
11
].
On the other hand, NPCs injected systemically in MCAo mice mostly maintain an
undifferentiated phenotype, while accumulating at the boundaries of the lesional area
[
61
,
62
]. Therefore, besides from the (limited) cell replacement, NPCs are believed to
exert tissue trophic and immune modulatory effects [
53
] also in stroke models. In line
with this, the subacute (delayed) NPC injection after MCAo has been shown to
significantly down regulate multiple RNA species involved in inflammation,
including IFN-c, TNF-a, IL-1b, IL-6, and leptin receptor [
62
]. NPCs may exert an
immune modulatory action, while in an undifferentiated state, causing a profound
down regulation of inflammatory lymphoid (T cells) and myeloid cells (macro-
phages) within inflamed brain areas. While the inhibition of the T cell responses by
NPCs is a quite established concept [
63
], the effects on microglia/macrophages at the
ischemic injury remain controversial, as professional phagocytes can exert both
