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Identifier 000419996
Title Two and Three-dimensional in vitro NSC34 models for ALS and pharmacological studies
Alternative Title Δισδιάστατα και τρισδιάστατα in vitro NSC34 κυτταρικά μοντέλα για την ALS και για φαρμακολογικές μελέτες
Author Σαρλίδου, Όλγα
Thesis advisor Γραβάνης, Αχιλλέας
Abstract Amyotrophic Lateral Sclerosis (ALS) is a fatal multifactorial neurodegenerative disorder with most patients dying within 5 years. Despite progress made in unraveling the pathophysiological mechanisms of ALS, no effective treatment has been found. So far only two drugs have received FDA approval for ALS (Riluzole, Edaravone), though both have limited effect on life expectancy. With most human clinical trials failing to demonstrate clinical efficacy, better pre-clinical models are required to save lives. This thesis utilizes a novel systems-level culture platform based on the NSC34 motor neuron-like cell like to evaluate various pro-apoptotic stimuli that mimic aspects of ALS pathophysiology (oxidative stress, excitotoxicity neuroinflammation) were investigated. Then, the effect of ALS FDA-approved or candidate drugs (Edaravone, BNN20) was evaluated. Experimental data based on high-content fluorescent imaging were consistent and reproducible. 24h or 48h serum deprivation and 48h of 100 ng/ml TNFα induced apoptosis and could be further incorporated to screen for novel neuroprotective compounds including novel microneurotrophins. NSC34 apoptosis induced by 100 μM H2O2 was not reversed upon Edaravone, BNN20 or BDNF treatment. The expression of TrkB and p75NTR receptors was confirmed in NSC34 cells, underling the potential of NSC34 utilization in TrkB - mediated pharmacological studies. Finally, this thesis presents the first steps towards developing a more physiologically relevant in vitro 3D cell culture model based on growing and studying NSC34 inside porous collagen scaffolds. Transition of NSC34 cell to 3D platform required seeding of C2C12 muscle cell line, as no NSC34 cell attachment to collagen occurred in the absence of C2C12. Further optimization of the NSC34 and C2C12 co-culture parameters (including cell differentiation, number, ratio and seeding as cell spheres or as single cells) demonstrated that differentiated single cells of both NSC34 and C2C12 provided the best results in terms of NSC34 adhesion to collagen and axonal growth.
Language English
Subject Matrigel sandwich culture
TRK receptors
Πορώδη ικριώματακολλαγόνου τύπου Ι
Issue date 2018-12-05
Collection   Faculty/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
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