LOTUS overexpression via ex vivo gene transduction further promotes recovery of motor function following human iPSC-NS/PC transplantation for contusive spinal cord injury.
LOTUS overexpression via ex vivo gene transduction further promotes recovery of motor function following human iPSC-NS/PC transplantation for contusive spinal cord injury.
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DOI：
10.1016/j.stemcr.2021.09.006
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发表时间：
2021-11-09
影响因子：
5.9
通讯作者：
Okano H
中科院分区：
文献类型：
--
作者：
Ito S;Nagoshi N;Kamata Y;Kojima K;Nori S;Matsumoto M;Takei K;Nakamura M;Okano H
功能恢复仍然受到限制，主要是由于多种机制，例如当人诱导多能干细胞衍生的神经干/祖细胞（hiPSC-NS/PC）被移植用于亚急性脊髓损伤（SCI）时，Nogo受体1（NgR1）信号的激活。我们之前报道了使用转基因小鼠在受损脊髓中过度表达侧嗅束引导物质（LOTUS）（一种内源性 NgR1 拮抗剂）的神经保护和再生益处。在这里，我们评估了在亚急性 SCI 小鼠模型中移植前将 LOTUS 基因慢病毒转导至 hiPSC-NS/PC 的效果。转导的 LOTUS 有助于神经突延伸、抑制细胞凋亡和体外神经营养因子的分泌。在体内，hiPSC-NS/PC 可增强移植细胞的存活率并增强移植细胞的轴突延伸，从而显着恢复 SCI 后的运动功能。因此，在 hiPSC-NS/PC 中进行 LOTUS 基因转导可能成为 SCI 移植治疗的一种有前途的辅助手段。 LOTUS 过表达 hiPSC-NS/PC 诱导轴突延伸和细胞凋亡抑制 LOTUS 过表达 hiPSC-NS/PC 增加神经营养因子的分泌 移植的 LOTUS 过表达 hiPSC-NS/PC 增强运动功能恢复 提供 LOTUS 的离体基因治疗有利于细胞移植 在本文中，Hideyuki Okano 和他的同事（Ito 等人）表明，转导的 LOTUS 有助于神经突形成hiPSC-NS/PC 的体外延伸、细胞凋亡抑制和神经营养因子的分泌。他们还表明，移植的 LOTUS 过表达 hiPSC-NS/PC 可增强移植细胞的存活率并增强移植细胞的轴突延伸，从而导致 SCI 后运动功能的显着恢复。
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. LOTUS-overexpressing hiPSC-NS/PCs induce axonal extension and apoptosis suppression LOTUS-overexpressing hiPSC-NS/PCs increase secretion of neurotrophic factors Transplanted LOTUS-overexpressing hiPSC-NS/PCs enhance motor functional recovery Ex vivo gene therapy delivering LOTUS is beneficial for cell transplantation In this article, Hideyuki Okano and his colleagues (Ito et al.) show that the transduced LOTUS contributes to neurite extension, apoptosis suppression, and secretion of neurotrophic factors in hiPSC-NS/PCs in vitro. They also show that transplanted LOTUS-overexpressing hiPSC-NS/PCs enhance survival of grafted cells and enhance axonal extension of the transplanted cells, resulting in significant restoration of motor function following SCI.
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