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

Jingwei Zheng; Haijian Wu; Xiaoyu Wang; Guoqiang Zhang; Jia'nan Lu; Weilin Xu; Shenbin Xu; Yuanjian Fang; Anke Zhang; Anwen Shao; Sheng Chen; Zhen Zhao; Jianmin Zhang; Jun Yu

doi:10.1016/j.jpha.2023.02.007

Volume 13 Issue 8

Aug. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(8): 862-879

Jingwei Zheng, Haijian Wu, Xiaoyu Wang, Guoqiang Zhang, Jia'nan Lu, Weilin Xu, Shenbin Xu, Yuanjian Fang, Anke Zhang, Anwen Shao, Sheng Chen, Zhen Zhao, Jianmin Zhang, Jun Yu. Temporal dynamics of microglia-astrocyte interaction in neuroprotective glial scar formation after intracerebral hemorrhage[J]. Journal of Pharmaceutical Analysis, 2023, 13(8): 862-879. doi: 10.1016/j.jpha.2023.02.007

Citation:

Jingwei Zheng, Haijian Wu, Xiaoyu Wang, Guoqiang Zhang, Jia'nan Lu, Weilin Xu, Shenbin Xu, Yuanjian Fang, Anke Zhang, Anwen Shao, Sheng Chen, Zhen Zhao, Jianmin Zhang, Jun Yu. Temporal dynamics of microglia-astrocyte interaction in neuroprotective glial scar formation after intracerebral hemorrhage[J]. Journal of Pharmaceutical Analysis, 2023, 13(8): 862-879. doi: 10.1016/j.jpha.2023.02.007

Citation:

Jingwei Zheng, Haijian Wu, Xiaoyu Wang, Guoqiang Zhang, Jia'nan Lu, Weilin Xu, Shenbin Xu, Yuanjian Fang, Anke Zhang, Anwen Shao, Sheng Chen, Zhen Zhao, Jianmin Zhang, Jun Yu. Temporal dynamics of microglia-astrocyte interaction in neuroprotective glial scar formation after intracerebral hemorrhage[J]. Journal of Pharmaceutical Analysis, 2023, 13(8): 862-879. doi: 10.1016/j.jpha.2023.02.007

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

doi: 10.1016/j.jpha.2023.02.007

Jingwei Zheng^a,c,
Haijian Wu^a,c,
Xiaoyu Wang^a,
Guoqiang Zhang^a,
Jia'nan Lu^a,
Weilin Xu^a,c,
Shenbin Xu^a,c,
Yuanjian Fang^a,c,
Anke Zhang^a,
Anwen Shao^a,c,
Sheng Chen^a,c,
Zhen Zhao^d,
Jianmin Zhang^{a,b,c
,
,},
Jun Yu^{a,c
,
,}

a. Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China;
b. Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310000, China;
c. Stroke Research Center for Diagnostic and Therapeutic Technologies of Zhejiang Province, Hangzhou, 310000, China;
d. Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA

Funds:

This study was supported by the National Natural Science Foundation of China (Grant Nos.: 82071287 and 81870916), the National Natural Science Foundation of China (Grant No.: 81971097), the Basic Public Interests Research Plan of Zhejiang Province, China (Grant No.: GF18H090006), the National Natural Science Foundation of China (Grant No.: 81701214), the National Natural Science Foundation of China (Grant No.: 82001299), and the Natural Science Foundation of Zhejiang Province, China (Grant No.: TGD23C040017).

Received Date: Oct. 08, 2022
Rev Recd Date: Feb. 02, 2023

Abstract

Abstract

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 early-stage ICH. Inversely, early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy. This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes, and develop elaborate treatment strategies at precise time points after ICH.
- Microglia,
- Astrocytes,
- Glial scar,
- Intracerebral hemorrhage

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References(64)

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