Abstract
Clearance of myelin debris caused by acute demyelination is an essential process for functional restoration following spinal cord injury (SCI). Microvascular endothelial cells, acting as “amateur” phagocytes, have been confirmed to engulf and degrade myelin debris, promoting the inflammatory response, robust angiogenesis, and persistent fibrosis. However, the effect of myelin debris engulfment on the function of endothelial tight junctions (TJs) remains unclear. Here, we demonstrate that myelin debris uptake impairs TJs and gap junctions of endothelial cells in the lesion core of the injured spinal cord and in vitro, resulting in increased permeability and leakage. We further show that myelin debris acts as an inducer to regulate the endothelial-to-mesenchymal transition in a dose-dependent manner and promotes endothelial cell migration through the PI3K/AKT and ERK signaling pathways. Together, our results indicate that myelin debris engulfment impairs TJs and promotes the migration of endothelial cells. Accelerating myelin debris clearance may help maintain blood–spinal cord barrier integrity, thus facilitating restoration of motor and sensory function following SCI.
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The data are available from the corresponding authors upon reasonable request.
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Acknowledgements
We are grateful for the support of the Scientific Research and Experimental Center of the Second Affiliated Hospital of Anhui Medical University. We thank BioRender (BioRender.com) for Fig. 9.
Funding
This work was founded by the Key Research and Development Program of Anhui Province (Grant Nos. 202004j07020042), the National Natural Science Foundation of China (Grant Nos. 81801220 and 81671204), and the Provincial Natural Science Research Key Project of Colleges and Universities of Anhui Province (Grant No. KJ2019A0257).
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JJ, MZ, and LC designed and supervised the study. FY, YL (2nd author), YC and YL (4th author) performed the experiments and data analysis with technical help from XH, XY, ZL, and YS. FY, YL (2nd author), ZL and DT edited and revised the manuscript. All authors have approved the final submitted manuscript.
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The animal study was reviewed and approved by the Animal Ethics Committee of Anhui Medical University.
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Yao, F., Luo, Y., Chen, Y. et al. Myelin Debris Impairs Tight Junctions and Promotes the Migration of Microvascular Endothelial Cells in the Injured Spinal Cord. Cell Mol Neurobiol 43, 741–756 (2023). https://doi.org/10.1007/s10571-022-01203-w
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DOI: https://doi.org/10.1007/s10571-022-01203-w