Abstract
Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by neuronal loss and motor dysfunction. Although there is no effective treatment, stem cell transplantation offers a promising therapeutic strategy, but the safety and efficacy of this approach needs to be optimized. The purpose of this study was to test the potential of intra-striatal transplantation of induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) for treating HD. For this purpose, we developed mouse adenovirus-generated iPSCs, differentiated them into neural stem cells in vitro, labeled them with Hoechst, and transplanted them bilaterally into striata of 10-month old wild type (WT) and HD YAC128 mice. We assessed the efficiency of these transplanted iPS-NSCs to reduce motor deficits in YAC128 mice by testing them on an accelerating rotarod task at 1 day prior to transplantation, and then weekly for 10 weeks. Our results showed an amelioration of locomotor deficits in YAC128 mice that received iPS-NSC transplantations. Following testing, the mice were sacrificed, and their brains were analyzed using immunohistochemistry and Western blot (WB). The results from our histological examinations revealed no signs of tumors and evidence that many iPS-NSCs survived and differentiated into region-specific neurons (medium spiny neurons) in both WT and HD mice, as confirmed by co-labeling of Hoechst-labeled transplanted cells with NeuN and DARPP-32. Also, counts of Hoechst-labeled cells revealed that a higher proportion were co-labeled with DARPP-32 and NeuN in HD-, compared to WT- mice, suggesting a dissimilar differentiation pattern in HD mice. Whereas significant decreases were found in counts of NeuN- and DARPP-32-labeled cells, and for neuronal density measures in striata of HD vehicle controls, such decrements were not observed in the iPS-NSCs-transplanted-HD mice. WB analysis showed increase of BDNF and TrkB levels in striata of transplanted HD mice compared to HD vehicle controls. Collectively, our data suggest that iPS-NSCs may provide an effective option for neuronal replacement therapy in HD.
Highlights
Huntington’s disease (HD) is a progressive, neurodegenerative, genetic disorder characterized by choreic movements, behavioral and cognitive disturbances, and dementia (Craufurd et al, 2001)
To test the efficacy of iPS-Neural stem cell (NSC) transplantations, we generated Induced pluripotent stem cells (iPSC) from WT mice and differentiated them to NSCs
The histological and motor deficits that are seen in the YAC128 mouse model recapitulates the HD changes in human HD patients, which makes this model ideal for assessing therapeutic interventions (Slow et al, 2003)
Summary
Huntington’s disease (HD) is a progressive, neurodegenerative, genetic disorder characterized by choreic movements, behavioral and cognitive disturbances, and dementia (Craufurd et al, 2001). The disease is caused by an autosomal dominant mutation in the huntingtin gene (HTT), and the mode of inheritance is dominant with almost full penetration (with 40 or more CAG repeats). The genetic basis of HD was discovered in 1993 (MacDonald et al, 1993), and it was found to be caused by an elongated Cystosine-Adenine-Guanine (CAG) repeat on the short arm of chromosome 4p16.3 in the HTT gene. As the disease progresses, symptoms become predictable, with all patients eventually developing same characteristic pathologies (Walker, 2007). The life expectancy for HD patients ranges between 15 and 20 years after the appearance of motor symptoms (Landles and Bates, 2004; Walker, 2007). Medium spiny neurons (MSNs) in the striatum appear to be the most vulnerable neurons to the damage in HD (Albin et al, 1990)
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