Abstract

Objective. Mesenchymal stem cell (MSC) therapy has been explored in Huntington disease (HD) as a potential therapeutic approach; however, a complete synthesis of these results is lacking. We conducted a meta-analysis to evaluate the effects of MSCs on HD. Method. Eligible studies published before November 2022 were screened from Embase, PubMed, Web of Science, Medline, and Cochrane in accordance with PRISMA guidelines. ClinicalTrial.gov and the World Health Organization International Clinical Trials Registry Platform were also searched for registered clinical trials. The outcomes in rodent studies evaluated included morphological changes (striatal volume and ventricular volume), motor function (rotarod test, wire hang test, grip strength test, limb-clasping test, apomorphine-induced rotation test, and neuromuscular electromyography activity), cognition (Morris water maze test), and body weight. Result. The initial search returned 362 records, of which 15 studies incorporating 346 HD rodents were eligible for meta-analysis. Larger striatal and smaller ventricular volumes were observed in MSC-treated animals compared to controls. MSCs transplanted before the occurrence of motor dysfunction rescued the motor incoordination of HD. Among different MSC sources, bone marrow mesenchymal stem cells were the most investigated cells and were effective in improving motor coordination. MSC therapy improved muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed. The body weight of male HD rodents increased after MSC transplantation, while that of females was not affected. Conclusion. Meta-analysis showed a positive effect of MSCs on HD rodents overall, as reflected in morphological changes, motor coordination, muscle strength, neuromuscular electromyography activity, cortex-related motor function, and striatum-related motor function, while cognition was not changed by MSC therapy.

Introduction

Huntington disease (HD) is a neurodegenerative disorder of the central nervous system resulting from a dominantly inherited CAG trinucleotide repeat expansion in exon 1 of the huntingtin (HTT) gene that encodes the Huntingtin protein [1]. Pathological changes are characterized by a general shrinkage of the brain and distinct degeneration of the striatum (caudate nucleus and putamen) [2]. Although HD prevalence is only 4-10 individuals per 100,000, it seriously affects the life quality of the patients in many ways, including movement, cognition, and psychological condition, as well as other functional disabilities [3]. Motor defects typically include chorea and loss of coordination. Psychiatric symptoms, such as depression, psychosis, and obsessive-compulsive disorder, are common in HD [4]. Death typically occurs about 20 years after symptom onset [1].

Current therapies for HD are directed at symptom relief, as there are no any disease-modifying therapies. Therapeutic attempts based on pathogenic mechanisms including gene silencing [5], antiapoptosis/caspase inhibition [6], transglutaminase inhibition [7], antioxidative stress [8], upregulating autophagy [9], and physical exercise [10] have been investigated; unfortunately, none of these have met the criteria for clinical translation. For instance, silencing the expression of the mutant HTT gene is attractive; however, allele specificity and off-target effects are not fully resolved. Treatment of mouse models with antioxidants was considered to be beneficial [8], whereas trials of creatine for symptomatic patients were disappointing [11].

Conclusion

This meta-analysis reveals MSC therapy attenuates morphological changes and improves motor function in HD models, but cognition was not influenced. Furthermore, the weight of male, but not female, HD rodents may be benefited from MSC treatment. These results support MSC-based strategies becoming an alternative treatment for HD; however, before MSC therapies can be translated into clinical practice, their safety, efficacy, and mechanism must be established with more preclinical and clinical studies.