Macrophage transplantation rescues RNASET2-deficient leukodystrophy by replacing deficient microglia in a zebrafish model

• 成果类型: Article
• 署名作者: Rutherford, Holly A.; Candeias, Diogo; Duncan, Christopher J. A.; Renshaw, Stephen A.; Hamilton, Noemie
• 署名单位: University of Sheffield; University of Sheffield; University of York - UK; University of York - UK; Newcastle University - UK; Newcastle University - UK; Newcastle Upon Tyne Hospitals NHS Foundation Trust
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14918
• DOI: 10.1073/pnas.2321496121
• 发表日期: 2024-05-21
• 关键词: stem-cell transplantation; metachromatic leukodystrophy; cystic leukoencephalopathy; mouse model; brain; reveal; SYSTEM

摘要

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 the rnaset2 mutant 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- restoring rnaset2 mutant 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 in rnaset2 mutants 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.