该课题组研究人员开发了包含人类CAMP热点突变的motheme模型，并通过骨髓移植替代小胶质细胞（Mr BMT）将CSF1R缺陷小胶质细胞替换为CSF1R正常细胞，从而减轻了小鼠的病理。该研究组进一步证明，在CSF1R缺乏的情况下，ALSP患者的传统骨髓移植（tBMT）功能与Mr BMT相似，有效地替代小胶质细胞并减少疾病进展。然后，课题组用tBMT替代了8名患者的CSF1R缺陷小胶质细胞。在24个月的随访期间，疾病进展停止。总之，在小鼠和人类中，小胶质细胞替代纠正了致病突变并阻止了疾病的进展。
研究人员表示，集落刺激因子1受体（CSF1R）主要在小胶质细胞中表达。它的单等位基因突变与CSF1R相关的小胶质病（CAMP）有关，CAMP是一种主要的成人发病脑白质病，伴轴突球体和色素胶质（ALSP），是一种无法临床治愈的致命神经系统疾病。
附：英文原文
Title: Microglia replacement halts the progression of microgliopathy in mice and humans
Author: Jingying Wu, Yafei Wang, Xiaoyu Li, Pei Ouyang, Yuanyuan Cai, Yang He, Mengyuan Zhang, Xinghua Luan, Yuxiao Jin, Jie Wang, Yujie Xiao, Yuqing Liang, Fang Xie, Yousheng Shu, Jiong Hu, Chunkang Chang, Jieling Jiang, Dong Wu, Youshan Zhao, Taohui Liu, Yuxin Li, Xiaojun Huang, Yao Li, Junfang Zhang, Yuwen Cao, Xin Cheng, Ying Mao, Yanxia Rao, Li Cao, Bo Peng
Issue&Volume: 2025-07-10
Abstract: 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.
DOI: adr1015
Source: https://www.science.org/doi/10.1126/science.adr1015