Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Stem Cells Transl Med. 2023 Mar 3;12(2):83-96. doi: 10.1093/stcltm/szac089.
Cell transplantation therapy using human-induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) is a new therapeutic strategy for spinal cord injury (SCI). Preclinical studies have demonstrated the efficacy of hiPSC-NS/PCs transplantation in the subacute phase of SCI. However, locomotor recovery secondary to hiPSC-NS/PCs transplantation is limited in the chronic phase, suggesting that additional treatment, including rehabilitative training, is required to ensure recovery. The therapeutic potential of hiPSC-NS/PCs that qualify for clinical application is yet to be fully delineated. Therefore, in this study, we investigated the therapeutic effect of the combined therapy of clinical-grade hiPSC-NS/PCs transplantation and rehabilitative training that could produce synergistic effects in a rodent model of chronic SCI. Our findings indicated that rehabilitative training promoted the survival rate and neuronal differentiation of transplanted hiPSC-NS/PCs. The combination therapy was able to enhance the expressions of the BDNF and NT-3 proteins in the spinal cord tissue. Moreover, rehabilitation promoted neuronal activity and increased 5-HT-positive fibers at the lumbar enlargement. Consequently, the combination therapy significantly improved motor functions. The findings of this study suggest that the combined therapy of hiPSC-NS/PCs transplantation and rehabilitative training has the potential to promote functional recovery even when initiated during chronic SCI.
利用人诱导多能干细胞衍生的神经干细胞/祖细胞(hiPSC-NS/PCs)进行细胞移植治疗是脊髓损伤(SCI)的一种新的治疗策略。临床前研究已经证明了 hiPSC-NS/PCs 移植在 SCI 亚急性期的疗效。然而,hiPSC-NS/PCs 移植后的运动功能恢复在慢性期是有限的,这表明需要额外的治疗,包括康复训练,以确保恢复。有资格进行临床应用的 hiPSC-NS/PCs 的治疗潜力尚未得到充分描绘。因此,在这项研究中,我们研究了临床级 hiPSC-NS/PCs 移植和康复训练联合治疗在慢性 SCI 啮齿动物模型中产生协同作用的治疗效果。我们的研究结果表明,康复训练促进了移植的 hiPSC-NS/PCs 的存活率和神经元分化。联合治疗能够增强脊髓组织中 BDNF 和 NT-3 蛋白的表达。此外,康复促进了腰膨大处神经元活动和 5-HT 阳性纤维的增加。因此,联合治疗显著改善了运动功能。这项研究的结果表明,即使在慢性 SCI 开始时,hiPSC-NS/PCs 移植和康复训练的联合治疗也有可能促进功能恢复。
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