Temporal dynamics of microglia-astrocyte interaction in neuroprotective glial scar formation after intracerebral hemorrhage

作者：Jingwei Zheng, Haijian Wu, Xiaoyu Wang, Guoqiang Zhang, Jianan Lü, Weilin Xu, Shenbin Xu, Yuanjian Fang, Anke Zhang, Anwen Shao, Sheng Chen, Zhen Zhao, Jianmin Zhang, Jun Yu · 发表于：Journal of Pharmaceutical Analysis · 年份：2023 · DOI：10.1016/j.jpha.2023.02.007 · 被引用次数：51 · 研究领域：Intracerebral and Subarachnoid Hemorrhage Research、Intracranial Aneurysms: Treatment and Complications、Immune cells in cancer

The role of glial scar after intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar. We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation. Spatial transcriptomics (ST) analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods. During the early stage, sustained microglial depletion induced disorganized astrocytic scar, enhanced neutrophil infiltration, and impaired tissue repair. ST analysis indicated that microglia-derived insulin like growth factor 1 (IGF1) modulated astrocytic scar formation via mechanistic target of rapamycin (mTOR) signaling activation. Moreover, repopulating microglia (RM) more strongly activated mTOR signaling, facilitating a more protective scar formation. The combination of IGF1 and osteopontin (OPN) was necessary and sufficient for RM function, rather than IGF1 or OPN alone. At the chronic stage of ICH, the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this. The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for ...