Abstract
Spinal cord injury (SCI) often results in various long-term sequelae, and chronically injured spinal cords exhibit a refractory feature, showing a limited response to cell transplantation therapies. To our knowledge, no preclinical studies have reported a treatment approach with results surpassing those of treatment comprising rehabilitation alone. In this study of rats with SCI, we propose a novel combined therapy involving a semaphorin 3A inhibitor (Sema3Ai), which enhances axonal regeneration, as the third treatment element in combination with neural stem/progenitor cell transplantation and rehabilitation. This comprehensive therapeutic strategy achieved significant improvements in host-derived neuronal and oligodendrocyte differentiation at the SCI epicenter and promoted axonal regeneration even in the chronically injured spinal cord. The elongated axons established functional electrical connections, contributing to significant enhancements in locomotor mobility when compared with animals treated with transplantation and rehabilitation. As a result, our combined transplantation, Sema3Ai, and rehabilitation treatment has the potential to serve as a critical step forward for chronic SCI patients, improving their ability to regain motor function.
Significant Statement Spinal cord injury (SCI) sometimes results in a fatal condition that often results in multiple disabilities, including paralysis. Numerous treatment approaches have been investigated for acute-phase SCI in rodents, but reports on the treatment of the chronic phase are limited. We compared three synergistic treatment elements—transplantation, rehabilitation, and medication—to combined transplantation and rehabilitation in rats with chronic SCI. Before treatment, both groups had insufficient hindlimb function in open-field walking. Hindlimb function with axonal regeneration of host tissue significantly improved in the combined transplantation, rehabilitation, and medication group, whereas the combined transplantation and rehabilitation group showed no such improvement. These results suggest that the triple combined treatment improves locomotor function and has potential for improving gait appearance in chronic SCI patients.
Footnotes
We appreciate the assistance, comments and instruction provided by Drs. R. Shibata, K. Kajikawa, Y. Kamata, M. Kawai, T. Kitagawa, K. Ago, T. Nishijima, Y. Saijo, Y. Suematsu, K. Ito, T. Tanaka, and all the members of the Spinal Cord Research Team at the Department of Orthopedic Surgery and Physiology, Keio University School of Medicine, Tokyo, Japan. We thank Prof. S. Yamanaka from Kyoto University, Kyoto, Japan for the human iPSC clones, and Sumitomo Pharma. (Hyogo, Japan) for providing the SM-345431. We also thank K. Yasutake, M. Akizawa, T. Kobayashi, and T. Harada from Department of Orthopedic Surgery, Keio University School of Medicine for their assistance with the experiments and animal care.
The authors declare no competing financial interests.
This research was supported by Japan Agency for Medical Research and Development (AMED) (grant Nos. JP15bm0204001 and JP23bm1223008).
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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