Cold protection allows local cryotherapy in a clinical-relevant model of traumatic optic neuropathy

  1. Yikui Zhang  Is a corresponding author
  2. Mengyun Li
  3. Bo Yu
  4. Shengjian Lu
  5. Lujie Zhang
  6. Senmiao Zhu
  7. Zhonghao Yu
  8. Tian Xia
  9. Haoliang Huang
  10. WenHao Jiang
  11. Si Zhang
  12. Lanfang Sun
  13. Qian Ye
  14. Jiaying Sun
  15. Hui Zhu
  16. Pingping Huang
  17. Huifeng Hong
  18. Shuaishuai Yu
  19. Wenjie Li
  20. Danni Ai
  21. Jingfan Fan
  22. Wentao Li
  23. Hong Song
  24. Lei Xu
  25. Xiwen Chen
  26. Tongke Chen
  27. Meng Zhou
  28. Jingxing Ou
  29. Jian Yang  Is a corresponding author
  30. Wei Li  Is a corresponding author
  31. Yang Hu  Is a corresponding author
  32. Wencan Wu  Is a corresponding author
  1. Wenzhou Medical University, China
  2. Beijing Institute of Technology, China
  3. Stanford University, United States
  4. Second Affiliated Hospital, Wenzhou Medical University, China
  5. Third Affiliated Hospital of Sun Yat-sen University, China
  6. National Eye Institute (NIH), United States

Abstract

Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: 1) Many of the CNS injury sites, such as the optic nerve (ON), are deeply buried, preventing access for local TH. The alternative is to apply TH systemically, which significantly limits the applicable temperature range. 2) Even with possible access for “local refrigeration”, cold-induced cellular damage offsets the benefit of TH. Here we present a clinically translatable model of traumatic optic neuropathy (TON) by applying clinical trans-nasal endoscopic surgery to goats and non-human primates. This model faithfully recapitulates clinical features of TON such as the injury site (pre-chiasmatic ON), the spatiotemporal pattern of neural degeneration, and the accessibility of local treatments with large operating space. We also developed a computer program to simplify the endoscopic procedure and expand this model to other large animal species. Moreover, applying a cold-protective treatment, inspired by our previous hibernation research, enables us to deliver deep hypothermia (4°C) locally to mitigate inflammation and metabolic stress (indicated by the transcriptomic changes after injury) without cold-induced cellular damage, and confers prominent neuroprotection both structurally and functionally. Intriguingly, neither treatment alone was effective, demonstrating that in situ deep hypothermia combined with cold protection constitutes a breakthrough for TH as a therapy for TON and other CNS traumas.

Data availability

Computer program download site:https://github.com/LujieZhang/Preoperative-planning.The processed gene expression data in this paper have been deposited into the NCBI GEO database: GSE182164. RNA-seq data download site: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE182164.

The following data sets were generated

Article and author information

Author details

  1. Yikui Zhang

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    For correspondence
    zhang.yikui@wmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  2. Mengyun Li

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Bo Yu

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Shengjian Lu

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Lujie Zhang

    Beijing Engineering Research Center of Mixed Reality and Advanced Display, Beijing Institute of Technology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Senmiao Zhu

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhonghao Yu

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Tian Xia

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Haoliang Huang

    Department of Ophthalmology, Stanford University, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. WenHao Jiang

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Si Zhang

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Lanfang Sun

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Qian Ye

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Jiaying Sun

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Hui Zhu

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Pingping Huang

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  17. Huifeng Hong

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Shuaishuai Yu

    School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  19. Wenjie Li

    Beijing Engineering Research Center of Mixed Reality and Advanced Display, Beijing Institute of Technology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  20. Danni Ai

    Beijing Engineering Research Center of Mixed Reality and Advanced Display, Beijing Institute of Technology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  21. Jingfan Fan

    Beijing Engineering Research Center of Mixed Reality and Advanced Display, Beijing Institute of Technology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  22. Wentao Li

    School of Computer Science and Technology, Beijing Institute of Technology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  23. Hong Song

    School of Computer Science and Technology, Beijing Institute of Technology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  24. Lei Xu

    Medical Radiology Department, Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  25. Xiwen Chen

    Animal Facility Center, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  26. Tongke Chen

    Animal Facility Center, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  27. Meng Zhou

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  28. Jingxing Ou

    Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  29. Jian Yang

    Beijing Engineering Research Center of Mixed Reality and Advanced Display, Beijing Institute of Technology, Beijing, China
    For correspondence
    jyang@bit.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  30. Wei Li

    Retinal Neurophysiology Section, National Eye Institute (NIH), Bethesda, United States
    For correspondence
    liwei2@nei.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2897-649X
  31. Yang Hu

    Department of Ophthalmology, Stanford University, Palo Alto, United States
    For correspondence
    huyang@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7980-1649
  32. Wencan Wu

    School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China
    For correspondence
    wuwencan@wmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Key Research and Development Program of China Stem Cell and Translational Research (2021YFA1101200)

  • Wencan Wu

National Key Research and Development Program of China (2016YFC1101200)

  • Wencan Wu

National Natural Science Foundation of China (81770926)

  • Wencan Wu

National Natural Science Foundation of China (81800842)

  • Yikui Zhang

Key R&D Program of Zhejiang Province (2018C03G2090634)

  • Wencan Wu

Key R&D Program of Zhejiang Province (2021C03065)

  • Wencan Wu

Key R&D Program of Wenzhou Eye Hospital (YNZD1201902)

  • Wencan Wu

National Key Research and Development Program of China (2019YFC0119300)

  • Jian Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments were conducted following the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research guidelines.All protocols were approved by the Institutional Animal Care and Use Committee in the Wenzhou Medical University (Wenzhou, China, ID number: wydw2020-0789) and the Joinn Laboratory (Suzhou, China, ID number: P19-S445-PD).

Reviewing Editor

  1. Paloma B Liton, Duke University School of Medicine, United States

Publication history

  1. Received: October 28, 2021
  2. Preprint posted: November 8, 2021 (view preprint)
  3. Accepted: March 29, 2022
  4. Accepted Manuscript published: March 30, 2022 (version 1)
  5. Version of Record published: May 4, 2022 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Yikui Zhang
  2. Mengyun Li
  3. Bo Yu
  4. Shengjian Lu
  5. Lujie Zhang
  6. Senmiao Zhu
  7. Zhonghao Yu
  8. Tian Xia
  9. Haoliang Huang
  10. WenHao Jiang
  11. Si Zhang
  12. Lanfang Sun
  13. Qian Ye
  14. Jiaying Sun
  15. Hui Zhu
  16. Pingping Huang
  17. Huifeng Hong
  18. Shuaishuai Yu
  19. Wenjie Li
  20. Danni Ai
  21. Jingfan Fan
  22. Wentao Li
  23. Hong Song
  24. Lei Xu
  25. Xiwen Chen
  26. Tongke Chen
  27. Meng Zhou
  28. Jingxing Ou
  29. Jian Yang
  30. Wei Li
  31. Yang Hu
  32. Wencan Wu
(2022)
Cold protection allows local cryotherapy in a clinical-relevant model of traumatic optic neuropathy
eLife 11:e75070.
https://doi.org/10.7554/eLife.75070

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