Further treatment strategies to enhance regenerative rehabilitation for cell therapy in chronic spinal cord injury: a concise review of preclinical studies

Tashiro, Syoichi1,2,*

1Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku, Japan

2Department of Rehabilitation Medicine, Kyorin University Faculty of Medicine, Mitaka, Japan

*Correspondence to: Syoichi Tashiro, MD, PhD, s-tashiro@keio.jp.

Abstract

Spinal cord injury causes longitudinal motor, sensory, and autonomic dysfunctions. Despite advances in cell therapies, regenerative capacity in the injured spinal cord remains minimal, especially in the chronic phase, necessitating innovative therapeutic strategies. Rehabilitation, through physical exercise and functional training, enhances motor function by upregulating neurotrophic factors and promoting plasticity, serving as a complementary or standalone treatment. Although synergistic effects between cell transplantation and rehabilitation are evident, the treatment efficacy of regenerative rehabilitation remains limited in the chronic phase. On this basis, the current review aims to summarize the recovery mechanism that works in the chronically injured spinal cord and further treatment strategies to enhance the effect of combination treatment with cell transplantation and rehabilitation. The current literature search revealed four studies that combined cell transplantation and rehabilitation in the definite chronic phase, all of which used neural stem/progenitor cells. Furthermore, only one of those four studies applied additional treatment, the axonal regeneration inhibitor semaphorin 3A. Studies have revealed that the promotion of cell differentiation and survival; the upregulation of neurotrophic factors; the increase in central pattern excitability, GABAergic capacity, synapse formation and axonal regeneration; and the reduction in pain pathway fibers are the background mechanisms of combination treatment with neural stem/progenitor cells and rehabilitation. However, the effect does not remarkably exceed that of single rehabilitation treatment in the chronic phase. Further combination with a sustained-releasing axonal regeneration inhibitor has yielded significant motor enhancement in chronic spinal cord injury models. Challenges persist, including insufficient axonal growth from graft-derived neurons and suboptimal recovery compared with subacute-phase outcomes. Tailored combinations of cell transplantation, rehabilitation, pharmacological interventions, and advanced modalities, such as scaffolding and physical stimulation therapy, will hold promise for overcoming refractory features of the chronically injured spinal cord and offer hope for meaningful recovery in patients with chronic spinal cord injury.

慢性脊髓损伤细胞疗法及再生康复的进一步治疗策略：临床前研究综述

摘要：

脊髓损伤会导致纵向运动、感觉和自主神经功能障碍。尽管细胞疗法取得了进展，但损伤脊髓的再生能力仍然微乎其微，尤其是在慢性期，因此需要创新的治疗策略。通过体育锻炼和功能训练进行康复治疗，可上调神经营养因子并促进可塑性，从而增强运动功能，既可作为辅助治疗，也可作为独立治疗。虽然细胞移植和康复治疗的协同作用明显，但再生康复治疗在慢性期的疗效似乎仍然有限。在此基础上，此综述旨在总结慢性损伤脊髓的恢复机制，以及进一步的治疗策略，以提高细胞移植与康复的联合治疗效果。目前的文献检索确定了4项在明确的慢性期结合细胞移植和康复治疗的研究，所有这些研究都使用了神经干细胞/祖细胞。此外，这4项研究中只有一项采用了额外的治疗方法，即轴突再生抑制剂Semaphorin 3A抑制剂。研究表明，促进细胞分化和存活、上调神经营养因子、提高中枢模式兴奋性、GABA能能力、突触形成和轴突再生、减少疼痛通路纤维是神经干/祖细胞与康复联合治疗的背景机制。然而，在慢性期，其效果并没有明显超过单一康复治疗。与轴突再生抑制剂的持续释放抑制剂进一步结合，可显著增强慢性脊髓损伤模型的运动能力。挑战依然存在，包括移植神经元的轴突生长不足，以及与亚急性期结果相比恢复情况不理想。细胞移植、康复、药物干预以及支架和物理刺激疗法等先进模式的定制组合将有望克服慢性损伤脊髓的难治性特征，并为慢性脊髓损伤患者的有效康复带来希望。