Abstract
BackgroundMachado-Joseph disease is the most common autosomal dominant hereditary ataxia worldwide without effective treatment. Mesenchymal stem cells (MSCs) could slow the disease progression, but side effects limited their clinical application. Besides, MSC-derived exosomes exerted similar efficacy and have many advantages over MSCs. The aim of this study was to examine the efficacy of MSC-derived exosomes in YACMJD84.2 mice.MethodsRotarod performance was evaluated every 2 weeks after a presymptomatic administration of intravenous MSC-derived exosomes twice in YACMJD84.2 mice. Loss of Purkinje cells, relative expression level of Bcl-2/Bax, cerebellar myelin loss, and neuroinflammation were assessed 8 weeks following treatment.ResultsMSC-derived exosomes were isolated and purified through anion exchange chromatography. Better coordination in rotarod performance was maintained for 6 weeks in YACMJD84.2 mice with exosomal treatment, compared with those without exosomal treatment. Neuropathological changes including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation were also attenuated 8 weeks after exosomal treatment. The higher relative ratio of Bcl-2/Bax was consistent with the attenuation of loss of Purkinje cells.ConclusionsMSC-derived exosomes could promote rotarod performance and attenuate neuropathology, including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation. Therefore, MSC-derived exosomes have a great potential in the treatment of Machado-Joseph disease.
Highlights
Machado-Joseph disease is the most common autosomal dominant hereditary ataxia worldwide without effective treatment
We aim to investigate whether Mesenchymal stem cells (MSCs)-derived exosomes can slow down the disease progression in a transgenic mouse model of Machado-Joseph disease (MJD)
We found that exosomes could improve rotarod performance, as well as attenuate neuropathology including loss of Purkinje cells, demyelination, and neuroinflammation
Summary
Machado-Joseph disease is the most common autosomal dominant hereditary ataxia worldwide without effective treatment. Clinical symptoms include progressive cerebellar ataxia, ophthalmoplegia, dysarthria, spasticity, and peripheral neuropathy. It is caused by CAG repeat expansion in the MJD1 gene, which encodes ATAXN3 protein. MSC-derived exosomes have many advantages over MSCs, including higher efficiency of passing through the blood-brain barrier, longer half-life period, lower immunogenicity, higher stability, and easier storage and transportation conditions [13]. Their effects have been proven to be comparable with MSCs in different models of neurological diseases [14, 15]
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