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Suppressing HTT production with antisense oligonucleotides (ASOs) is a promising treatment strategy for HD; however, the difficulty of delivering ASOs to deep brain structures is a major barrier for its clinical application. The glymphatic system of astrocytes involving aquaporin 4 (AQP-4) controls the entry of macromolecules from the cerebrospinal fluid into the brain. Mesenchymal stem cells (MSCs) target astrocytes to inhibit neuroinflammation. Here we examined the glymphatic distribution of ASO in the brain and the therapeutic potential of combining intravenously injection of mesenchymal stem cells (IV-MSC) and ASOs for the treatment of HD. Our results show that Cy3-labeled ASOs entered the brain parenchyma via the perivascular space following cisternal injection, but the brain distribution was significantly lower in AQP-4\u2212\/\u2212 as compared with wild-type mice. Downregulation of the AQP-4\u2009M23 isoform was accompanied by decreased brain levels of ASOs in BACHD mice as well as an increase in astrogliosis and phosphorylation of nuclear factor \u03baB (NF-\u03baB) p65. IV-MSC treatment restored AQP-4\u2009M23 expression, attenuated astrogliosis, and decreased NF-\u03baB p65 phosphorylation; it also increased the brain distribution of ASOs and enhanced the suppression of mHTT in BACHD mice. These results suggest that modulating glymphatic activity using IV-MSC is a novel strategy for improving the potency of ASO in the treatment of HD.<\/jats:p>\n               <jats:sec>\n                  <jats:title\/>\n               <\/jats:sec>","DOI":"10.1002\/stem.3103","type":"journal-article","created":{"date-parts":[[2019,10,24]],"date-time":"2019-10-24T18:05:29Z","timestamp":1571940329000},"page":"218-230","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice"],"prefix":"10.1093","volume":"38","author":[{"given":"Teng-teng","family":"Wu","sequence":"first","affiliation":[{"name":"a Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-juan","family":"Su","sequence":"additional","affiliation":[{"name":"a Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-qing","family":"Feng","sequence":"additional","affiliation":[{"name":"a Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"b Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-yue","family":"Li","sequence":"additional","affiliation":[{"name":"c Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-yin","family":"Liang","sequence":"additional","affiliation":[{"name":"a Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Li","sequence":"additional","affiliation":[{"name":"d Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-jiao","family":"Li","sequence":"additional","affiliation":[{"name":"d Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"d Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong, People's Republic of 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