The Department of Neurology, the Agnes Ginges Center for Human Neurogenetics, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Centre for Clinical Brain Sciences, MS Centre, University of Edinburgh, Edinburgh, EH16 4SB, UK.
Mol Neurobiol. 2020 Feb;57(2):1021-1034. doi: 10.1007/s12035-019-01802-7. Epub 2019 Oct 28.
Neuroglial precursor cells (NPC) possess immune-modulatory properties by which they prevent immune-mediated injury in experimental autoimmune encephalomyelitis (EAE). It is unclear whether cell transplantation in a clinical-relevant setup induces ongoing therapeutic effects in a chronic-active model of progressive multiple sclerosis (MS). We examined whether human embryonic stem cell (hESC)-derived NPCs inhibit progressive EAE in Biozzi AB/H mice, manifesting with chronic-active neuroinflammation and demyelinated plaques. hESC-derived NPCs were propagated for 6-8 weeks as spheres enriched for Olig2+ cells to switch from neuronal to glial commitment and to enrich for oligodendrocyte progenitor cells. NPC were transplanted intracerebroventricularly at 30 days post-EAE induction, after the acute relapse. We evaluated effects of cell transplantation on clinical parameters, neuroinflammation, myelination, and axonal loss. Transplanted animals exhibited a significantly milder disease, reduced neuroinflammation, reduced demyelination, and reduced axonal loss as compared to control EAE mice. Toluidine-blue semi-thin staining showed a bystander neuroprotective effect of human precursor cells preventing the loss of myelinated fibers in superficial layer of the cervical dorsal funiculus. Human Olig2+ cells were detected along spinal cord meninges after 65 days of follow-up. In co-cultures in vitro, Olig2+ human precursors inhibited Concanavalin A-induced murine T cell activation and proliferation. To conclude, glial-committed human NPC induce ongoing immune-regulatory and neuroprotective effects, following transplantation into mice with a clinical-relevant model of chronic-active MS and during established disease, entering the chronic phase. These properties highlight the therapeutic potential of human NPC transplantation in chronic MS and their delivery via the cerebrospinal fluid.
神经胶质前体细胞（NPC）具有免疫调节特性，可防止实验性自身免疫性脑脊髓炎（EAE）中的免疫介导损伤。尚不清楚在临床相关设置中进行细胞移植是否会在进行性多发性硬化（MS）的慢性活跃模型中引起持续的治疗效果。我们研究了人胚胎干细胞（hESC）衍生的 NPC 是否可以抑制表现出慢性活跃性神经炎症和脱髓鞘斑块的 Biozzi AB/H 小鼠中的进行性 EAE。hESC 衍生的 NPC 在诱导 EAE 后 30 天进行脑室内移植，此时处于急性复发后。我们评估了细胞移植对临床参数、神经炎症、髓鞘形成和轴突丢失的影响。与对照 EAE 小鼠相比，移植的动物表现出明显较轻的疾病、减少的神经炎症、减少的脱髓鞘和减少的轴突丢失。甲苯胺蓝半薄染色显示人前体细胞具有旁观者神经保护作用，可防止颈背索浅表层髓鞘纤维的丢失。在 65 天的随访后，在脊髓脑膜中检测到人类 Olig2+细胞。在体外共培养中，Olig2+人类前体细胞抑制刀豆蛋白 A 诱导的小鼠 T 细胞激活和增殖。总之，胶质分化的人类 NPC 在移植到具有临床相关慢性活跃 MS 模型的小鼠中以及在已建立的疾病中会持续诱导免疫调节和神经保护作用，进入慢性期。这些特性突出了人 NPC 移植在慢性 MS 中的治疗潜力及其通过脑脊液的递呈。
