Epidural Spinal Cord Stimulation Promotes Motor Functional Recovery by Enhancing Oligodendrocyte Survival and Differentiation and by Protecting Myelin after Spinal Cord Injury in Rats
Gang Li 1,2 • Zhong-Kai Fan 3 • Guang-Fei Gu 1,2 • Zhi-Qiang Jia 4 • Qiang-Qiang Zhang 3 • Jun-Yu Dai 3 • Shi-Sheng He 1,2
1 Department of Orthopedics, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
2 Spinal Pain Research Institute, Tongji University School of Medicine, Shanghai 200072, China
3 Department of Orthopaedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou 121001, China
4 Department of Spinal Surgery, The Second Affiliated Hospital, Henan University of Science and Technology, Luoyang 471003, China
Epidural spinal cord stimulation (ESCS) markedly improves motor and sensory function after spinal cord injury (SCI), but the underlying mechanisms are unclear. Here, we investigated whether ESCS affects oligodendrocyte differentiation and its cellular and molecular mechanisms in rats with SCI. ESCS improved hindlimb motor function at 7 days, 14 days, 21 days, and 28 days after SCI. ESCS also significantly increased the myelinated area at 28 days, and reduced the number of apoptotic cells in the spinal white matter at 7 days. SCI decreased the expression of 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase, an oligodendrocyte marker) at 7 days and that of myelin basic protein at 28 days. ESCS significantly upregulated these markers and increased the percentage of Sox2/CNPase/DAPI-positive cells (newly differentiated oligodendrocytes) at 7 days. Recombinant human bone morphogenetic protein 4 (rhBMP4) markedly downregulated these factors after ESCS. Furthermore, ESCS significantly decreased BMP4 and p-Smad1/5/9 expression after SCI, and rhBMP4 reduced this effect of ESCS. These findings indicate that ESCS enhances the survival and differentiation of oligodendrocytes, protects myelin, and promotes motor functional recovery by inhibiting the BMP4-Smad1/5/9 signaling pathway after SCI.
Spinal cord injury; Epidural spinal cord stimulation; Oligodendrocyte; Differentiation; Remyelination