Microglia replacement halts the progression of microgliopathy in mice and humans

• 成果类型: Article
• 署名作者: Wu, Jingying; Wang, Yafei; Li, Xiaoyu; Ouyang, Pei; Cai, Yuanyuan; He, Yang; Zhang, Mengyuan; Luan, Xinghua; Jin, Yuxiao; Wang, Jie; Xiao, Yujie; Liang, Yuqing; Xie, Fang; Shu, Yousheng; Hu, Jiong; Chang, Chunkang; Jiang, Jieling; Wu, Dong; Zhao, Youshan; Liu, Taohui; Li, Yuxin; Huang, Xiaojun; Li, Yao; Zhang, Junfang; Cao, Yuwen; Cheng, Xin; Mao, Ying; Rao, Yanxia; Cao, Li; Peng, Bo
• 署名单位: Shanghai Jiao Tong University; Fudan University; Fudan University; Fudan University; Fudan University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Fudan University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12584
• DOI: 10.1126/science.adr1015
• 发表日期: 2025-07-10
• 关键词: stimulating factor-i; hereditary diffuse leukoencephalopathy; adult-onset leukoencephalopathy; axonal spheroids; pigmented glia; csf-1 receptor; tyrosine; mouse; cell; differentiation

摘要

Colony-stimulating factor 1 receptor (CSF1R) is primarily expressed in microglia. Its monoallelic mutation causes CSF1R-associated microgliopathy (CAMP), a major form of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and a fatal neurological disease without clinical cure. We developed mouse models harboring human hotspot mutations of CAMP and replaced CSF1R-deficient microglia with CSF1R-normal cells through microglia replacement by bone marrow transplantation (Mr BMT), which attenuated pathology in mice. We further demonstrated that, in the context of CSF1R deficiency, traditional bone marrow transplantation (tBMT) in ALSP functions similarly to Mr BMT, efficiently replacing microglia and reducing disease progression. We then replaced CSF1R-deficient microglia in eight patients by tBMT. The disease progression was halted during the 24-month follow-up. Together, microglia replacement corrects pathogenic mutations and halts disease progression in mice and humans.