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康复训练增强人诱导多能干细胞源性神经干细胞/祖细胞移植治疗慢性脊髓损伤的疗效

Rehabilitative Training Enhances Therapeutic Effect of Human-iPSC-Derived Neural Stem/Progenitor Cells Transplantation in Chronic Spinal Cord Injury.

机构信息

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.

出版信息

Stem Cells Transl Med. 2023 Mar 3;12(2):83-96. doi: 10.1093/stcltm/szac089.


DOI:10.1093/stcltm/szac089
PMID:36647673
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9985116/
Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/fca0c0f92927/szac089f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/db9f4f601e1e/szac089f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/ed7bedb8610a/szac089f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/45c8a5d38728/szac089f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/f2be9e867418/szac089f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/5858c6144ad5/szac089f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/532861ff39d7/szac089f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/431419bbc1ff/szac089f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/fca0c0f92927/szac089f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/db9f4f601e1e/szac089f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/ed7bedb8610a/szac089f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/45c8a5d38728/szac089f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/f2be9e867418/szac089f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/5858c6144ad5/szac089f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/532861ff39d7/szac089f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/431419bbc1ff/szac089f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4363/9985116/fca0c0f92927/szac089f0007.jpg

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[4]
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[5]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Regenerative Rehabilitation and Stem Cell Therapy Targeting Chronic Spinal Cord Injury: A Review of Preclinical Studies.

Cells. 2022-2-16

[2]
Modulation by DREADD reveals the therapeutic effect of human iPSC-derived neuronal activity on functional recovery after spinal cord injury.

Stem Cell Reports. 2022-1-11

[3]
Current progress of rehabilitative strategies in stem cell therapy for spinal cord injury: a review.

NPJ Regen Med. 2021-11-25

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Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function.

Cell Rep. 2021-11-23

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Cells. 2021-10-6

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First-in-human clinical trial of transplantation of iPSC-derived NS/PCs in subacute complete spinal cord injury: Study protocol.

Regen Ther. 2021-9-7

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Int J Rehabil Res. 2021-12-1

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Treadmill training based on the overload principle promotes locomotor recovery in a mouse model of chronic spinal cord injury.

Exp Neurol. 2021-11

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Current Concepts of Stem Cell Therapy for Chronic Spinal Cord Injury.

Int J Mol Sci. 2021-7-11

[10]
Neurorehabilitation using a voluntary driven exoskeletal robot improves trunk function in patients with chronic spinal cord injury: a single-arm study.

Neural Regen Res. 2022-2

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