Abstract
Intrastriatal administration of mesenchymal stem cells (MSCs) has shown beneficial effects in rodent models of Huntington disease (HD). However, the invasive nature of surgical procedure and its potential to trigger the host immune response may limit its clinical use. Hence, we sought to evaluate the non-invasive intranasal administration (INA) of MSC delivery as an effective alternative route in HD. GFP-expressing MSCs derived from bone marrow were intranasally administered to 4-week-old R6/2 HD transgenic mice. MSCs were detected in the olfactory bulb, midbrain and striatum five days post-delivery. Compared to phosphate-buffered saline (PBS)-treated littermates, MSC-treated R6/2 mice showed an increased survival rate and attenuated circadian activity disruption assessed by locomotor activity. MSCs increased the protein expression of DARPP-32 and tyrosine hydroxylase (TH) and downregulated gene expression of inflammatory modulators in the brain 7.5 weeks after INA. While vehicle treated R6/2 mice displayed decreased Iba1 expression and altered microglial morphology in comparison to the wild type littermates, MSCs restored both, Iba1 level and the thickness of microglial processes in the striatum of R6/2 mice. Our results demonstrate significantly ameliorated phenotypes of R6/2 mice after MSCs administration via INA, suggesting this method as an effective delivering route of cells to the brain for HD therapy.
Highlights
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder that affects 4–10 individuals per 100,000 [1,2,3,4]
R6/2 mice as well as showing a trend towards improved motor function; (3) mesenchymal stem cells (MSCs) treatment in R6/2 mice increased DARPP-32 expression in the striatum while the expression levels of synaptic markers and neuron-specific nuclear protein (NeuN) remained unchanged; (4) all investigated immunomodulators were either significantly restored or showed a trend towards restoration in most of the brain areas examined after MSCs treatment; and (5) neuroprotective effects of MSC were concomitant with increased expression of Ionized calcium-binding adapter molecule 1 (Iba1) in the striatum and restored morphology of striatum-resident microglia of R6/2 mice
As we have shown that the dopaminergic system in R6/2 mice benefited from the MSCs treatment, we did not pursue deeper into the precise molecular mechanisms of MSCs treatment on circadian control in this study, the remedial effects of MSCs suggest a causal link between MSCs and circadian rhythm correction, probably via the restoration of functional dopamine signaling on circadian genes induction/expression
Summary
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder that affects 4–10 individuals per 100,000 [1,2,3,4]. HTT gene that contains approximately 145 CAG repeats (length of polyglutamine expansion varies due to germ line instability) [46,47] As a result, they display physiological and behavioral phenotypes that recapitulate symptoms of HD patients [48,49], including progressive weight loss, shortened life span [46,50,51], progressive motor dysfunction [50,52], cognitive decline [53,54] and neuropsychiatric-like disturbances [55,56] such as disrupted circadian rhythm [57]. Our study provides evidence that intranasal administration of MSCs is an efficacious delivery route for HD treatment and has a high translational potential to the clinics for HD as well as other neurodegeneration-targeting therapies
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