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|Autori: ||Vicario, Nunzio|
|Titolo: ||Directly induced Neural Stem Cells transplantation and prospects for stem cell-based therapy|
|Abstract: ||Despite the remarkable beneficial effects of disease-modifying agents in relapsing-remitting multiple
sclerosis (MS) patients, progressive forms of (P)MS still lack effective treatments. This stark contrast is
partially dependent on the difficulties researchers have found in tackling the complex pathophysiology of this
phase of disease, in which chronic inflammation within the central nervous system (CNS) is coupled by
ongoing neurodegeneration and demyelination.
Cell transplantation is among the most promising therapeutic approaches in regenerative medicine,
combining tissue trophic and immunomodulatory effects of the graft with its intrinsic potential for cellreplacement.
These are all attributes that can be harnessed to treated patients with PMS.
As such, within this thesis, I have focused my attention on investigating how cellular therapies could be used
to (i) prevent neuronal damage, (ii) modulate the chronic activation of the immune system and (iii) replace
the damaged myelin in PMS.
Olfactory Ensheathing Cells (OECs) are a special population of glial cells known to exert neuroprotective
mechanisms and capable of promoting neuroprotection. Using in vitro models of neuron-like cells, I have
demonstrated that OECs exert their neuroprotective effect by reducing Cx43-mediated cell-to-cell and cell-toextracellular
environment communications. Despite this important finding, the immunomodulatory and
remyelinating potential of OECs is still limited. As such, I decided to study a complementary stem cell
approach that conjugates these attributes with ease in clinical applicability.
Induced Neural Stem Cells (iNSCs) are a source of autologous, stably expandable, tissue specific and easily
accessible stem cells, which have the potential to differentiate into the three main neural lineages. Mouse
iNSCs were characterized in vitro and in vivo and their immunomodulatory potential was initially studied. This
work uncovered a novel mechanism that underpins the potential of iNSCs to interact with the chronic CNS
compartmentalised activation of the innate immune system. Specifically, I found that iNSCs are able to
sense extracellular metabolites, which accumulate in the chronically inflamed CNS, and to ameliorate
neuroinflammation via succinate-SUCNR1-dependend mechanisms. To characterize the potential for tissue
replacement and remyelination of such a promising cell line, I have also analysed how iNSCs grafts
differentiate in an experimental model of focal demyelination. I found that iNSCs are able to integrate and
differentiate into remyelinating oligodendrocytes (OLs) in chronic demyelinated CNS. These data suggest
that iNSCs are indeed an effective source of stem cell transplantation, being able to modulate inflammation
and to effectively replace lost tissue in mouse models of PMS.
Altogether the evidences gathered in this thesis are important new steps in the field of cell transplantation,
which will be pivotal in the march forward for future clinical applications in chronic demyelinating CNS
|In||Area 06 - Scienze mediche|
|VCRNNZ89P18C351N-PhD_Final Dissertation VICARIO NUNZIO.pdf||PhD dissertation_Vicario Nunzio||9,16 MB||Adobe PDF||Visualizza/apri
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