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HGSNAT is a transmembrane enzyme incapable of free diffusion between the cells or their cross-correction, which limits development of therapies based on enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages\/microglia derived from a heterologous HSPC transplant. Eight-week-old MPS IIIC (HgsnatP304L) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied using behavior test battery, starting from the age of 6 months. At the age of ~8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage, and other biomarkers of the disease. We found that the treatment corrected several behavior deficits including hyperactivity and reduction in socialization, but not memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1\u03b2, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels. Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with cells from a normal healthy donor. They also suggest that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology.<\/jats:p>","DOI":"10.3390\/cells13100877","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T03:26:27Z","timestamp":1716261987000},"page":"877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Heterologous HSPC Transplantation Rescues Neuroinflammation and Ameliorates Peripheral Manifestations in the Mouse Model of Lysosomal Transmembrane Enzyme Deficiency, MPS IIIC"],"prefix":"10.3390","volume":"13","author":[{"given":"Xuefang","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0803-569X","authenticated-orcid":false,"given":"Antoine","family":"Caillon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxian","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaukat","family":"Khan","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-2160","authenticated-orcid":false,"given":"Shunji","family":"Tomatsu","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-1062","authenticated-orcid":false,"given":"Alexey V.","family":"Pshezhetsky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s10545-011-9436-z","article-title":"Newborn Screening for Lysosomal Diseases: Current Status and Potential Interface with Population Medical Genetics in Latin America","volume":"35","author":"Giugliani","year":"2012","journal-title":"J. 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