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Inhibition of Epidermal Growth Factor Receptor Improves Myelination and Attenuates Tissue Damage of Spinal Cord Injury

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Abstract

Preventing demyelination and promoting remyelination of denuded axons are promising therapeutic strategies for spinal cord injury (SCI). Epidermal growth factor receptor (EGFR) inhibition was reported to benefit the neural functional recovery and the axon regeneration after SCI. However, its role in de- and remyelination of axons in injured spinal cord is unclear. In the present study, we evaluated the effects of EGFR inhibitor, PD168393 (PD), on the myelination in mouse contusive SCI model. We found that expression of myelin basic protein (MBP) in the injured spinal cords of PD treated mice was remarkably elevated. The density of glial precursor cells and oligodendrocytes (OLs) was increased and the cell apoptosis in lesions was attenuated after PD168393 treatment. Moreover, PD168393 treatment reduced both the numbers of OX42 + microglial cells and glial fibrillary acidic protein + astrocytes in damaged area of spinal cords. We thus conclude that the therapeutic effects of EGFR inhibition after SCI involves facilitating remyelination of the injured spinal cord, increasing of oligodendrocyte precursor cells and OLs, as well as suppressing the activation of astrocytes and microglia/macrophages.

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Funding

The study was funded by National Natural Science Foundation of China (No. 81470053) and Natural Science Foundation of Shanghai, China (No. 14ZR1435900).

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    Authors and Affiliations

    1. School of Life Science and Technology, Xinxiang Medical University, Jinsui Road, Xinxiang, 453003, Henan, China

      Si Zhang & Zhiwei Feng

    2. Brain Research Center, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada

      Si Zhang

    3. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 201108, China

      Peijun Ju

    4. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore

      Editha Tjandra & Hamed Owlanj

    5. Cytogenetics Laboratory, Singapore General Hospital, Singapore, Singapore

      Yeeshan Yeap

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    1. Si Zhang
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    Correspondence to Zhiwei Feng.

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    Ethical approval

    All procedures performed in the study involving animals were in accordance with the ethical standards of Institutional Animal Care and Use Committee of Nanyang Technological University, Singapore and Xinxiang Medical University, China.

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    Si Zhang and Peijun Ju contributed equally to the paper.

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    10571_2015_313_MOESM1_ESM.tif

    Supplementary material 1 (TIF 13915 kb). Fig. S1 PD effectively reduces pEGFR +/OX42 + macrophages and pEGFR +/GFAP + astrocytes in 3 days post injury. Immunoflorescent images showed the pEGFR +/OX42 + (a-h), pEGFR +/GFAP + (i-p) cells in the injury epicenter in both control and PD-treated groups. Nuclei were counterstained with DAPI in all images. Examples of double labeled pEGFR +/OX42 + cells and pEGFR +/GFAP + cells in all the images were indicated by arrow. Scale bars 50 µm

    10571_2015_313_MOESM2_ESM.tif

    Supplementary material 2 (TIF 9201 kb). Fig. S2 EGFR inhibition induces more OPCs to express MBP post SCI. NG2 + (red) OPCs labeled with mature myelin marker MBP (green) was found in the white matter in the lesion site of control and PD-treated mice, as shown in the orthogonal view of a-j. Nuclei were counterstained with DAPI. Quantitative result further illustrated significant expression of NG2 and MBP at 3 and 7 days post SCI (k). Scale bars 10 µm

    10571_2015_313_MOESM3_ESM.tif

    Supplementary material 3 (TIF 840 kb). Fig. S3 PD alleviates oligodendrocytes apoptosis after SCI. Quantification of the number of apoptotic CC1 + oligodendrocytes within the 6 mm along rostral-caudal axis of spinal cord at 3 and 7 days post SCI (a) (n = 5, *P < 0.05). The proportion of caspase-3 +/CC1 + cells was determined by dividing the number of cells double-labeled for caspase-3 and CC1 by the number of CC1 + cells in control and PD-treated group respectively (b) (n = 5, *P < 0.05). Results represented the number of immunopositive cells per mm2

    Supplementary material 4 (PDF 12 kb)

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    Zhang, S., Ju, P., Tjandra, E. et al. Inhibition of Epidermal Growth Factor Receptor Improves Myelination and Attenuates Tissue Damage of Spinal Cord Injury. Cell Mol Neurobiol 36, 1169–1178 (2016). https://doi.org/10.1007/s10571-015-0313-4

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    • DOI: https://doi.org/10.1007/s10571-015-0313-4

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