2. Academic Validation
  3. Microglia replacement halts the progression of microgliopathy in mice and humans

Microglia replacement halts the progression of microgliopathy in mice and humans

  • Science. 2025 Jul 10;389(6756):eadr1015. doi: 10.1126/science.adr1015.
Jingying Wu # 1 2,  Yafei Wang # 2,  Xiaoyu Li # 2,  Pei Ouyang # 2 3,  Yuanyuan Cai 2,  Yang He 2,  Mengyuan Zhang 1 2,  Xinghua Luan 1 4,  Yuxiao Jin 3,  Jie Wang 5,  Yujie Xiao 2,  Yuqing Liang 6,  Fang Xie 5,  Yousheng Shu 2,  Jiong Hu 7,  Chunkang Chang 8,  Jieling Jiang 7,  Dong Wu 8,  Youshan Zhao 8,  Taohui Liu 2,  Yuxin Li 2,  Xiaojun Huang 1 4,  Yao Li 9,  Junfang Zhang 1 4,  Yuwen Cao 1 4,  Xin Cheng 1 4,  Ying Mao 10,  Yanxia Rao 3,  Li Cao 1 4,  Bo Peng 2 10
Affiliations

Affiliations

  • 1 Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 National Children's Medical Center, Children's Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai, China.
  • 3 Department of Neurology, Zhongshan Hospital, Laboratory Animal Center, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
  • 4 Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China.
  • 5 Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China.
  • 6 Department of Neurosurgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 Shanghai Institute of Hematology, Blood and Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8 Department of Hematology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9 National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
  • 10 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
  • # Contributed equally.
PMID: 40638739 DOI: 10.1126/science.adr1015
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.

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