Human-induced pluripotent stem cell-derived neural stem/progenitor cell ex vivo gene therapy with synaptic organizer CPTX for spinal cord injury.

IF 5.9 2区医学 Q1 CELL & TISSUE ENGINEERING

Stem Cell Reports Pub Date : 2024-03-12 Epub Date: 2024-02-15 DOI:10.1016/j.stemcr.2024.01.007

Yusuke Saijo, Narihito Nagoshi, Momotaro Kawai, Takahiro Kitagawa, Yu Suematsu, Masahiro Ozaki, Munehisa Shinozaki, Jun Kohyama, Shinsuke Shibata, Kosei Takeuchi, Masaya Nakamura, Michisuke Yuzaki, Hideyuki Okano

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Abstract

The transplantation of neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) has shown promise in spinal cord injury (SCI) model animals. Establishing a functional synaptic connection between the transplanted and host neurons is crucial for motor function recovery. To boost therapeutic outcomes, we developed an ex vivo gene therapy aimed at promoting synapse formation by expressing the synthetic excitatory synapse organizer CPTX in hiPSC-NS/PCs. Using an immunocompromised transgenic rat model of SCI, we evaluated the effects of transplanting CPTX-expressing hiPSC-NS/PCs using histological and functional analyses. Our findings revealed a significant increase in excitatory synapse formation at the transplantation site. Retrograde monosynaptic tracing indicated extensive integration of transplanted neurons into the surrounding neuronal tracts facilitated by CPTX. Consequently, locomotion and spinal cord conduction significantly improved. Thus, ex vivo gene therapy targeting synapse formation holds promise for future clinical applications and offers potential benefits to individuals with SCI.

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用突触组织者CPTX进行脊髓损伤的人诱导多能干细胞衍生神经干/祖细胞体外基因治疗。

移植源自人类诱导多能干细胞（hiPSCs）的神经干/祖细胞（NS/PCs）已在脊髓损伤（SCI）模型动物中显示出前景。在移植神经元和宿主神经元之间建立功能性突触连接对运动功能的恢复至关重要。为了提高治疗效果，我们开发了一种体外基因疗法，旨在通过在 hiPSC-NS/PCs 中表达合成兴奋性突触组织者 CPTX 来促进突触的形成。我们利用免疫受损的转基因 SCI 大鼠模型，通过组织学和功能分析评估了移植表达 CPTX 的 hiPSC-NS/PCs 的效果。我们的研究结果表明，移植部位兴奋性突触的形成明显增加。逆行单突触描记表明，CPTX 促进了移植神经元与周围神经元束的广泛整合。因此，运动和脊髓传导明显改善。因此，针对突触形成的体外基因疗法有望在未来应用于临床，并为脊髓损伤患者带来潜在的益处。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Stem Cell Reports CELL & TISSUE ENGINEERING-CELL BIOLOGY

CiteScore

10.50

自引率

1.70%

发文量

200

审稿时长

28 weeks

期刊介绍： Stem Cell Reports publishes high-quality, peer-reviewed research presenting conceptual or practical advances across the breadth of stem cell research and its applications to medicine. Our particular focus on shorter, single-point articles, timely publication, strong editorial decision-making and scientific input by leaders in the field and a "scoop protection" mechanism are reasons to submit your best papers.