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, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan.
Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Stem Cell Reports. 2021 Nov 9;16(11):2703-2717. doi: 10.1016/j.stemcr.2021.09.006. Epub 2021 Oct 14.
Functional recovery is still limited mainly due to several mechanisms, such as the activation of Nogo receptor-1 (NgR1) signaling, when human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PC) are transplanted for subacute spinal cord injury (SCI). We previously reported the neuroprotective and regenerative benefits of overexpression of lateral olfactory tract usher substance (LOTUS), an endogenous NgR1 antagonist, in the injured spinal cord using transgenic mice. Here, we evaluate the effects of lentiviral transduction of LOTUS gene into hiPSC-NS/PCs before transplantation in a mouse model of subacute SCI. The transduced LOTUS contributes to neurite extension, suppression of apoptosis, and secretion of neurotrophic factors in vitro. In vivo, the hiPSC-NS/PCs enhance the survival of grafted cells and enhance axonal extension of the transplanted cells, resulting in significant restoration of motor function following SCI. Therefore, the gene transduction of LOTUS in hiPSC-NS/PCs could be a promising adjunct for transplantation therapy for SCI.
功能恢复仍然受到多种机制的限制,例如 Nogo 受体-1(NgR1)信号的激活,当人诱导多能干细胞衍生的神经干细胞/祖细胞(hiPSC-NS/PC)被移植用于亚急性脊髓损伤(SCI)时。我们之前曾报道过使用转基因小鼠过表达外侧嗅束引导物质(LOTUS),一种内源性 NgR1 拮抗剂,对损伤脊髓的神经保护和再生作用。在这里,我们评估了在亚急性 SCI 小鼠模型中,将 LOTUS 基因转导到 hiPSC-NS/PC 之前对其进行慢病毒转导的效果。转导的 LOTUS 有助于体外轴突延伸、抑制细胞凋亡和神经营养因子的分泌。在体内,hiPSC-NS/PC 增强了移植细胞的存活,并增强了移植细胞的轴突延伸,从而导致 SCI 后运动功能的显著恢复。因此,将 LOTUS 基因转导到 hiPSC-NS/PC 中可能是 SCI 移植治疗的一种有前途的辅助手段。