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Inhibition of Astrocytic Carbohydrate Sulfotransferase 15 Promotes Nerve Repair After Spinal Cord Injury via Mitigation of CSPG Mediated Axonal Inhibition

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Abstract

Nerve tissue regeneration is a significant problem. After neural diseases and damage such as spinal cord injury (SCI), the accumulation of chondroitin sulfate proteoglycans (CSPG) comprising axonal inhibitory glycosaminoglycan chains in the microenvironment is a major barrier that obstructs nerve repair. Interfering with the production of glycosaminoglycans, especially the critical inhibitory chains, could be a potential therapeutic strategy for SCI, which is, however, poorly defined. This study identifies Chst15, the chondroitin sulfotransferase controlling the generation of axonal inhibitory chondroitin sulfate-E, as a therapeutic target of SCI. Using a recently reported small molecular Chst15 inhibitor, this study investigates the effects of Chst15 inhibition on astrocyte behaviors and the associated consequences of in vivo disruption of the inhibitory microenvironment. Deposition of CSPGs in the extracellular matrix and migration of astrocytes are both significantly impaired by Chst15 inhibition. Administration of the inhibitor in transected spinal cord tissues of rats effectively promotes motor functional restoration and nerve tissue regeneration by a mechanism related to the attenuation of inhibitory CSPGs, glial scar formation and inflammatory responses. This study highlights the role of Chst15 in the CSPG-mediated inhibition of neural recovery after SCI and proposes an effective neuroregenerative therapeutic strategy that uses Chst15 as a potential target.

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Data Availability

Datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank the Ocean University of China and the Pilot National Laboratory for Marine Science and Technology for the supports. This work was financially supported by the National Natural Science Foundation of China (22107095, 81803451), Natural Science Fund for Excellent Young Scholars of Shandong Province (ZR2021YQ53), and funded by Pilot National Laboratory for Marine Science and Technology (Qingdao) (JCZX202006).

Funding

This work was financially supported by the National Natural Science Foundation of China (22107095, 81803451), Natural Science Fund for Excellent Young Scholars of Shandong Province (ZR2021YQ53), and funded by Pilot National Laboratory for Marine Science and Technology (Qingdao) (JCZX202006).

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Author notes

  1. Liming Li and Heping Zheng have contributed equally.

Authors and Affiliations

  1. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266071, China

    Liming Li, Heping Zheng, Xuepei Ma, Jie Bai, Shumin Ma, Zhuoyue Li & Chong Qin

  2. Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, 266071, China

    Liming Li

  3. Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266137, China

    Chong Qin

  4. Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, 266003, China

    Chong Qin

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  1. Liming Li
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Contributions

The experiment conduction and the manuscript writing were finished through the contributions of all authors. The study conception and design were mainly from CQ and LL. Drug synthesis and characterization were completed by JB. LL, HZ, and JB performed the cellular and in vivo experiment, data collection, and data analysis. SM and ZL contributed to the manuscript editing, and the manuscript writing was accomplished mainly by LL under the participation of all authors. All the authors have approved the final version of the manuscript.

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Correspondence to Liming Li or Chong Qin.

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All animal experiments and procedures were conducted under the approval of the Institutional Animal Care and Use Committee at Ocean University of China.

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Li, L., Zheng, H., Ma, X. et al. Inhibition of Astrocytic Carbohydrate Sulfotransferase 15 Promotes Nerve Repair After Spinal Cord Injury via Mitigation of CSPG Mediated Axonal Inhibition. Cell Mol Neurobiol 43, 2925–2937 (2023). https://doi.org/10.1007/s10571-023-01333-9

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