Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Stem Cell Reports. 2023 Apr 11;18(4):899-914. doi: 10.1016/j.stemcr.2023.02.012. Epub 2023 Mar 23.
Cell replacement therapy is expected as a new and more radical treatment against brain damage. We previously reported that transplanted human cerebral organoids extend their axons along the corticospinal tract in rodent brains. The axons reached the spinal cord but were still sparse. Therefore, this study optimized the host brain environment by the adeno-associated virus (AAV)-mediated expression of axon guidance proteins in mouse brain. Among netrin-1, SEMA3, and L1CAM, only L1CAM significantly promoted the axonal extension of mouse embryonic brain tissue-derived grafts. L1CAM was also expressed by donor neurons, and this promotion was exerted in a haptotactic manner by their homophilic binding. Primary cortical neurons cocultured on L1CAM-expressing HEK-293 cells supported this mechanism. These results suggest that optimizing the host environment by the AAV-mediated expression of axon guidance molecules enhances the effect of cell replacement therapy.
细胞替代疗法有望成为一种新的、更激进的治疗脑损伤的方法。我们之前曾报道过，移植的人类脑类器官会沿着啮齿动物大脑中的皮质脊髓束延伸其轴突。这些轴突到达脊髓，但仍然稀疏。因此，本研究通过腺相关病毒（AAV）介导的在小鼠大脑中表达轴突导向蛋白来优化宿主大脑环境。在 netrin-1、SEMA3 和 L1CAM 中，只有 L1CAM 能显著促进源自小鼠胚胎脑组织移植物的轴突延伸。供体细胞神经元也表达 L1CAM，这种促进作用是通过它们的同种型结合以趋化的方式发挥的。在表达 L1CAM 的 HEK-293 细胞上共培养的原代皮质神经元支持这种机制。这些结果表明，通过 AAV 介导的轴突导向分子表达来优化宿主环境可以增强细胞替代疗法的效果。
