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Alzheimer disease (AD) is the most common cause of dementia and constitutes a major socioeconomic burden. As the underlying cause of AD remains unknown, the clinical need for disease modifying therapies is ever more pressing. Due to the low turnover of neural tissues and the extensive neurodegeneration associated with AD, regenerative medicine therapies are a promising strategy for the treatment of these patients [1]. Enhanced endogenous neurogenesis has been associated with a slower cognitive decline in humans and animal models [4]. Similarly, the delivery of exogenous stem cells has been shown to ameliorate the symptoms and lead to functional recovery [1]. However, limitations related to low cell survival and high immunogenicity significantly hinder clinical efficacy.
Electrical stimulation (ES) has been shown to modulate the proliferation and differentiation of neural stem cells (NSC) and thus, it holds high therapeutic potential [2]. Deep brain stimulation (DBS) is a well-established, FDA-approved approach that has been widely used for the treatment of neurodegenerative disorders. Although pre-clinical evidence has shown that DBS leads to slower cognitive decline in AD, the invasiveness of the approach precludes translation [5].
In this regard, DBS via temporally interfering (TI) electric fields has emerged as a promising strategy for non-invasive ES of neurons at depth. However, its influence on the proliferation and differentiation of NSCs and the effect of different stimulation paradigms remains unexplored.
A high-throughput device for in vitro ES based on TI was developed to study the influence of DBS on NSC fate. The effect of biomimetic ES paradigms on NSC proliferation and differentiation was investigated. Changes in the expression of stem-associated and lineage-specific biomarkers were evaluated using immunofluorescent staining. A stimulation frequency of 10 Hz, mimicking the activity in the developing brain, was proven to increase neuronal differentiation, proliferation, and metabolic activity of NSCs. Transcriptome analysis using mRNA-seq was carried out to investigate changes in gene expression following ES at this frequency. Spontaneous neural network activity in differentiated cultures of NSCs was evaluated using live calcium imaging.
The effect of this stimulation paradigm on the proliferation and differentiation of NSCs encapsulated in an injectable scaffold was also investigated. It has been hypothesised that the combinatorial effect of ES and endogenous microenvironmental cues can improve the survival and integration of exogenous stem cells. Therefore, NSCs were encapsulated in a bioactive, self-assembling hydrogel and stimulated in vitro with the optimised paradigm. The combinatorial effect of ES and the bioactive scaffolds on the maturation and functionality of the resulting neural networks was evaluated as described above.
An ES paradigm for the modulation of NSC fate was optimised in vitro using a bespoke high-throughput stimulation device, and an optimal frequency to enhance neuronal differentiation has been identified. A combinatorial strategy based on NSCs encapsulated in a self-assembling injectable scaffold for minimally invasive delivery and stimulation was also developed. This approach could constitute the basis for non-invasive DBS strategies for the treatment of AD and other neurodegenerative disorders, which can promote endogenous neuroregeneration or increase the efficacy of exogenous stem cell transplants.
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