Division of Biological Sciences, University of California - San Diego, La Jolla, CA, USA.
Department of Neurosciences, University of California - San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA.
Exp Neurol. 2019 Apr;314:46-57. doi: 10.1016/j.expneurol.2019.01.006. Epub 2019 Jan 15.
Neural stem cells (NSCs) can differentiate into both neurons and glia after transplantation into spinal cord injury (SCI) sites. The neuronal component of stem cell grafts has the potential to form functional synaptic relays across the lesion site. The glial component may reform a blood-spinal cord barrier, support neuronal function, and contribute to remyelination. We performed a long-term, 1.5-year time course study focused on astrocyte migration, differentiation, integration, and safety following human NSC transplantation into C5 hemisection sites in immunodeficient rats. NSCs that adopted a neuronal fate did not migrate from the lesion site. In contrast, transplanted cells that adopted astrocyte fates exhibited long distance migration from the lesion site through host white matter in rostrocaudal directions. These cells migrated slowly at a mean rate of 2-3 mm/month, divided as they migrated, and gradually differentiated into astrocytes. After 1.5 years, human astrocytes migrated nine spinal cord segments, caudally to the mid-thoracic level, and rostrally into the brainstem. The migrated human astrocytes joined the endogenous population of astrocytes in the host spinal cord, extended perivascular endfeet towards host pericytes and endothelium, formed interspecies and intraspecies perivascular astrocytic networks connected by gap junctions, and expressed glutamate transporter proteins in perisynaptic processes, suggesting structural and functional integration. No adverse consequences of this extended glial migration were detected. Adjacent to the lesion site, chronic host astrocytic upregulation was significantly attenuated by NSC grafts. Thus, human astrocytes can migrate long distances from sites of SCI and safely integrate into the host central nervous system. SIGNIFICANCE STATEMENT: Neural stem cell (NSC) grafts are a candidate therapy for spinal cord injury (SCI). Here we report an 18-month study of astrocyte survival and migration from sites of SCI in immunodeficient rats. NSC grafts significantly attenuate host astrocyte reactivity at the lesion/host interface. Intra-graft astrocytes integrate into the host blood-spinal cord barrier (BSCB) and widely express glutamate transporter proteins characteristic of neurotransmitter regulation. Notably, astrocytic components of NSC grafts exhibit gradual yet extensive migration after implantation into the mid-cervical injury site; neurons do not migrate at all. This extensive astrocyte migration is not detectably associated with adverse outcomes anatomically or behaviorally.
神经干细胞（NSCs）在移植到脊髓损伤（SCI）部位后可以分化为神经元和神经胶质细胞。干细胞移植的神经元成分有可能在病变部位形成功能性突触连接。神经胶质细胞可能重建血脊髓屏障，支持神经元功能，并有助于髓鞘形成。我们进行了一项为期 1.5 年的长期时间过程研究，重点研究了人类 NSCs 移植到免疫缺陷大鼠 C5 半切部位后，星形胶质细胞的迁移、分化、整合和安全性。采用神经元命运的 NSCs 不会从病变部位迁移。相比之下，采用星形胶质细胞命运的移植细胞通过宿主白质从病变部位向头尾部方向进行长距离迁移。这些细胞以平均 2-3mm/月的速度缓慢迁移，在迁移过程中分裂，并逐渐分化为星形胶质细胞。1.5 年后，人类星形胶质细胞向脊髓尾部迁移了 9 个脊髓节段，到达胸中段，向头部迁移进入脑干。迁移的人类星形胶质细胞加入了宿主脊髓内的内源性星形胶质细胞群，向宿主周细胞和内皮细胞延伸血管周足，形成由缝隙连接连接的种间和种内血管周星形胶质细胞网络，并在突触旁过程中表达谷氨酸转运蛋白，提示结构和功能整合。没有发现这种扩展的神经胶质迁移的不良后果。在病变部位附近，NSC 移植物显著减轻了慢性宿主星形胶质细胞的上调。因此，人类星形胶质细胞可以从 SCI 部位长距离迁移，并安全地整合到宿主中枢神经系统中。
神经干细胞（NSC）移植物是治疗脊髓损伤（SCI）的候选疗法。在这里，我们报告了一项在免疫缺陷大鼠 SCI 部位进行的星形胶质细胞存活和迁移的 18 个月研究。NSC 移植物显著减轻了病变/宿主界面处宿主星形胶质细胞的反应性。移植内星形胶质细胞整合到宿主血脊髓屏障（BSCB）中，并广泛表达具有神经递质调节特征的谷氨酸转运蛋白。值得注意的是，NSC 移植物在植入颈中部损伤部位后表现出逐渐但广泛的迁移；神经元根本不会迁移。这种广泛的星形胶质细胞迁移在解剖学或行为学上与不良后果无关。
