Macrophage transplantation rescues RNASET2-deficient leukodystrophy by replacing deficient microglia in a zebrafish model
Macrophage transplantation rescues RNASET2-deficient leukodystrophy by replacing deficient microglia in a zebrafish model
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巨噬细胞移植通过替换斑马鱼模型中缺陷的小胶质细胞来挽救 RNASET2 缺陷的脑白质营养不良
DOI：
10.1101/2023.12.04.569924
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Rutherford H
中科院分区：
文献类型：
--
作者：
Rutherford H
rnaset2缺陷性脑白质营养不良是一种罕见的婴儿白质疾病，类似于病毒感染，导致严重的精神运动障碍。尽管其严重，但对其细胞机制的了解很少，也没有治疗方法。最近使用thernaset2突变斑马鱼模型的研究表明，小胶质细胞可能是神经病理的驱动因素，因为它们在神经发育过程中不能消化凋亡碎片。因此，我们开发了一种通过将成人全肾骨髓源性巨噬细胞移植到胚胎宿主的小胶质细胞替代策略。通过实时成像，我们发现移植源性巨噬细胞可以植入宿主大脑并表达小胶质细胞特异性标记物，表明采用小胶质细胞表型。组织清除策略揭示了移植细胞在宿主大脑中超过胚胎阶段的持久性。我们证明，移植细胞清除脑内凋亡细胞，并挽救过度激活的抗病毒反应，否则在突变幼虫中看到。移植源性细胞植入峰值的RNA测序证实，在rnaset2缺陷的大脑中，移植可以降低全脑免疫反应，特别是抗病毒反应。至关重要的是，神经炎症的减少导致行为拯救-将胚胎和幼年期的grnaset2突变体的运动活动恢复到野生型（WT）水平。综上所述，这些发现证明了小胶质细胞作为神经病理突变的细胞驱动因素的作用，巨噬细胞移植是斑马鱼小胶质细胞替代的可行策略。因此，针对小胶质细胞的干预可能对rnaset2缺陷性脑白质营养不良有治疗作用。
RNASET2-deficient leukodystrophy is a rare infantile white matter disorder mimicking a viral infection and resulting in severe psychomotor impairments. Despite its severity, there is little understanding of cellular mechanisms of pathogenesis and no treatments. Recent research using thernaset2mutant zebrafish model has suggested that microglia may be the drivers of the neuropathology, due to their failure to digest apoptotic debris during neurodevelopment. Therefore, we developed a strategy for microglial replacement through transplantation of adult whole kidney marrow–derived macrophages into embryonic hosts. Using live imaging, we revealed that transplant-derived macrophages can engraft within host brains and express microglia-specific markers, suggesting the adoption of a microglial phenotype. Tissue-clearing strategies revealed the persistence of transplanted cells in host brains beyond embryonic stages. We demonstrated that transplanted cells clear apoptotic cells within the brain, as well as rescue overactivation of the antiviral response otherwise seen in mutant larvae. RNA sequencing at the point of peak transplant-derived cell engraftment confirms that transplantation can reduce the brain-wide immune response and particularly, the antiviral response, in rnaset2-deficient brains. Crucially, this reduction in neuroinflammation resulted in behavioral rescue—restoringrnaset2mutant motor activity to wild-type (WT) levels in embryonic and juvenile stages. Together, these findings demonstrate the role of microglia as the cellular drivers of neuropathology inrnaset2mutants and that macrophage transplantation is a viable strategy for microglial replacement in the zebrafish. Therefore, microglia-targeted interventions may have therapeutic benefits in RNASET2-deficient leukodystrophy.
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小胶质细胞消化发育凋亡细胞的失败有助于RNASET2缺陷型白细胞病的病理。
影响因子：
6.2
作者：
Hamilton N;Rutherford HA;Petts JJ;Isles HM;Weber T;Henneke M;Gärtner J;Dunning MJ;Renshaw SA
通讯作者：
Renshaw SA
DOI：
10.1093/bioinformatics/btac166
发表时间：
2022-05-13
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
通讯作者：
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影响因子：
8.8
作者：
Ferrero, Giuliano;Mahony, Christopher B.;Wittamer, Valerie
通讯作者：
Wittamer, Valerie
影响因子：
29
作者：
Groeschel, Samuel;Kuehl, Joern-Sven;Mueller, Ingo
通讯作者：
Mueller, Ingo
造血干细胞移植不会延缓迟发性异染性脑白质营养不良心理认知变异型的疾病进展
影响因子：
4.2
作者：
N. Smith;R. Marcus;B. Sahakian;N. Kapur;T. Cox
通讯作者：
T. Cox