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Inhibition of GPR17/ID2 Axis Improve Remyelination and Cognitive Recovery after SAH by Mediating OPC Differentiation in Rat Model

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Abstract

Myelin sheath injury contributes to cognitive deficits following subarachnoid hemorrhage (SAH). G protein-coupled receptor 17 (GPR17), a membrane receptor, negatively regulates oligodendrocyte precursor cell (OPC) differentiation in both developmental and pathological contexts. Nonetheless, GPR17's role in modulating OPC differentiation, facilitating remyelination post SAH, and its interaction with downstream molecules remain elusive. In a rat SAH model induced by arterial puncture, OPCs expressing GPR17 proliferated prominently by day 14 post-onset, coinciding with compromised myelin sheath integrity and cognitive deficits. Selective Gpr17 knockdown in oligodendrocytes (OLs) via adeno-associated virus (AAV) administration revealed that reduced GPR17 levels promoted OPC differentiation, restored myelin sheath integrity, and improved cognitive deficits by day 14 post-SAH. Moreover, GPR17 knockdown attenuated the elevated expression of the inhibitor of DNA binding 2 (ID2) post-SAH, suggesting a GPR17-ID2 regulatory axis. Bi-directional modulation of ID2 expression in OLs using AAV unveiled that elevated ID2 counteracted the restorative effects of GPR17 knockdown. This resulted in hindered differentiation, exacerbated myelin sheath impairment, and worsened cognitive deficits. These findings highlight the pivotal roles of GPR17 and ID2 in governing OPC differentiation and axonal remyelination post-SAH. This study positions GPR17 as a potential therapeutic target for SAH intervention. The interplay between GPR17 and ID2 introduces a novel avenue for ameliorating cognitive deficits post-SAH.

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Data Availability

The data that were used to support the findings of this study are not openly available to maintain privacy protection. However, the data can be made available from the corresponding author upon reasonable request. Researchers who are interested in accessing the data for scientific purposes can contact the corresponding author to request access.

Abbreviations

aSAH:

Aneurysmal subarachnoid hemorrhage

AAV:

Adeno-associated virus

ACA:

Anterior cerebral artery

AUC:

Area under the curve

BrdU:

Bromodeoxyuridine

CBF:

Cerebral blood flow

CC:

Corpus callosum

CCA:

Common carotid artery

CNS:

Central nervous system

EAE:

Experimental autoimmune encephalomyelitis

ECA:

External carotid artery

DCI:

Delayed cerebral ischemia

GPR17:

G protein-coupled receptor 17 (for protein)

Gpr17:

Gpr17 gene

ICA:

Internal carotid artery

IF:

Immunofluorescence

LFP:

Local field potential

MWM:

Morris water maze

MS:

Multiple sclerosis

NC:

Normal control

OGD:

Oxygen-glucose deprivation

OL:

Oligodendrocyte OPColigodendrocyte precursor cell

OPC:

Oligodendrocyte precursor cell

PSD:

Power spectral density

ROI:

Region of interest

ShG-V:

AAV2/9-control shRNA

ShG:

AAV2/9-Gpr17 shRNA

SGOI-V:

AAV2/9-Gpr17 shRNA + AAV2/9-NC control

SGOI:

AAV2/9-Gpr17 shRNA + AAV2/9-Id2 overexpression RNA

SGSI-V:

AAV2/9-Gpr17 shRNA + AAV2/9-control shRNA

SGSI:

AAV2/9-Gpr17 shRNA + AAV2/9-Id2 shRNA

TEM:

Transmission electron microscope

WB:

Western blotting

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Acknowledgements

The authors acknowledge the financial support provided by the National Natural Science Foundation of China, Chongqing Science and Health Joint Medical Research Project and the Science and Technology Research Program of Chongqing Municipal Education Commission.

Funding

• the National Natural Science Foundation of China (No.81901210 No.82071332 and No.82071397).

• the Key Project of Chongqing Science and Health Joint Medical Research Project (No.2020GDRC024).

• the Science and Technology Research Program of Chongqing Municipal Education Commission (No.KJQN202000428 and No.CYS22342).

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Author notes

  1. Yingwen Wang, Anan Jiang these authors contributed equally to this article.

Authors and Affiliations

  1. Department of Neurosurgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, China

    Yingwen Wang, Jin Yan, Nina Gu, Zhao Li, Xiaochuan Sun, Yue Wu & Zongduo Guo

  2. Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Anan Jiang

  3. Department of Neurosurgery, Xuanhan County People’s Hospital, Dazhou, China

    Daochen Wen

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  1. Yingwen Wang
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Contributions

• Yue Wu, Zongduo Guo and Xiaochuan Sun designed the experimental protocol.

• Yingwen Wang and Anan Jiang conducted the experiments.

• Jin Yan, Daochen Wen, Nina Gu, Zhao Li, participated in various experiment steps, including data collection and analysis.

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Correspondence to Yue Wu or Zongduo Guo.

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Wang, Y., Jiang, A., Yan, J. et al. Inhibition of GPR17/ID2 Axis Improve Remyelination and Cognitive Recovery after SAH by Mediating OPC Differentiation in Rat Model. Transl. Stroke Res. (2023). https://doi.org/10.1007/s12975-023-01201-0

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