Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Stem Cell Reports. 2024 Mar 12;19(3):383-398. doi: 10.1016/j.stemcr.2024.01.007. Epub 2024 Feb 15.
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.
源自人诱导多能干细胞（hiPSCs）的神经干细胞/祖细胞（NS/PCs）移植在脊髓损伤（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于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治疗方法，通过在 hiPSC-NS/PCs 中表达合成兴奋性突触组织者 CPTX 来促进突触形成。我们使用免疫缺陷型转基因 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。我们的发现表明，在移植部位兴奋性突触形成显著增加。逆行单突触追踪表明，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治疗有望应用于未来的临床应用，并为 SCI 患者带来潜在益处。
