Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (6): 2621-2631.doi: 10.4103/NRR.NRR-D-24-01400

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Delayed microglial depletion protects against white matter injury following neonatal cerebral hemorrhage in mice

Xiaoxiao Jing1, 2, #, Xiaoli Zhang2, #, Hongwei Li2, 3, 4, #, Yu Yang2, Zuhang Zhao1, Yuandan Li1, 2, Jinjin Zhu1, 2, Yiran Xu2, Jing Yuan2, Tiantian He2, Chen Zhang1, 2, Juan Song1, Xin Zhao5, Xiaoyang Wang2, 6, Changlian Zhu2, 7, *, Falin Xu1, 2, *   

  1. 1Department of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; 
    2Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; 
    3Department of Laboratory Medicine, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; 
    4Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, Zhengzhou, Henan Province, China; 
    5Department of Imaging, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; 
    6Center for Perinatal Medicine and Health, Institute of Clinical Science, University of Gothenburg, Gothenburg, Sweden; 
    7Center for Bran Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
  • Online:2026-06-15 Published:2026-04-17
  • Contact: Changlian Zhu, MD, PhD, changlian.zhu@neuro.gu.se; Falin Xu, MD, PhD, xufalin@zzu.edu.cn.
  • Supported by:
    This study was supported by the National Key Research and Development Program of China, No. 2022YFC2704801 (to CZhu); the National Natural Science Foundation of China, Nos. U21A20347 (to CZhu), 82203969 (to YX), 82371472 (to XZ); Health Commission of Henan Province, Nos. SBGJ202303039 (to XZ), SBGJ202301009 (to CZhu), YQRC2024018 (to XZ), YQRC2024019 (to YX); Henan Science and Technology Department, Nos. 242102311054 (to XZ), 241111521300 (to CZhu), GZS2023003 (to XW); Swedish Research Council, Nos. 2022-01019 (to CZhu), 2021-01950 (to XW); Swedish Governmental Grants to Scientists Working in Healthcare, Nos. ALFGBG-1005209 (to CZhu), ALFBG-1005257 (to XW), ALFGBG-965197 (to CZhu).

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Abstract: Germinal matrix hemorrhage in preterm neonates often leads to white matter injury, contributing to long-term neurodevelopmental impairments. As resident brain immune cells, microglia play a complex role in injury response, including inflammation and repair. Although colony-stimulating factor 1 receptor inhibitors such as PLX5622 enable the selective depletion of microglia, their therapeutic potential in neonatal germinal matrix hemorrhage remains underexplored. Here, we used a collagenase-induced germinal matrix hemorrhage model in postnatal day 5 mice, and intraperitoneally administered PLX5622 72 hours post–germinal matrix hemorrhage to achieve targeted, temporary microglial depletion during the peak injury response. We then assessed the effects of this delayed intervention on oligodendrocyte lineage cell maturation, white matter integrity, and neurobehavioral outcomes. Additionally, RNA sequencing data from a germinal matrix hemorrhage rat model were analyzed using weighted gene co-expression network analysis to identify the critical phases for interventions. RNA sequencing data revealed a critical period in which key synaptic functions declined while immune responses intensified post–germinal matrix hemorrhage, thus pinpointing the critical response phases for potential interventions. Delayed PLX5622 treatment effectively depleted activated microglia, protecting against white matter injury and enhancing oligodendrocyte lineage cell maturation and myelination in subcortical white matter regions. Moreover, magnetic resonance imaging analysis revealed reduced brain lesion volumes in treated mice. Behaviorally, PLX5622-treated mice exhibited significant improvements in motor coordination and reduced hyperactivity compared with vehicle-treated germinal matrix hemorrhage model mice. These findings suggest that, when timed to avoid interference with initial oligodendrocyte lineage cell proliferation, targeted microglial depletion with PLX5622 significantly mitigates white matter damage and improves neurobehavioral outcomes in neonatal germinal matrix hemorrhage. The present study highlights the therapeutic potential of selectively modulating microglial reactivity to support neurodevelopment in preterm infants with brain injury.

Key words: colony-stimulating factor 1 receptor, germinal matrix hemorrhage, microglia, myelination, neonatal brain, oligodendrocyte lineage cell, PLX5622, white matter injury