Chen Hong, Qian Kun, Chen Wei, Hu Baoyang, Blackbourn Lisle W, Du Zhongwei, Ma Lixiang, Liu Huisheng, Knobel Karla M, Ayala Melvin, Zhang Su-Chun
J Clin Invest. 2015 Mar 2;125(3):1033-42. doi: 10.1172/JCI69097. Epub 2015 Feb 2.
Astrocytes are integral components of the homeostatic neural network as well as active participants in pathogenesis of and recovery from nearly all neurological conditions. Evolutionarily, compared with lower vertebrates and nonhuman primates, humans have an increased astrocyte-to-neuron ratio; however, a lack of effective models has hindered the study of the complex roles of human astrocytes in intact adult animals. Here, we demonstrated that after transplantation into the cervical spinal cords of adult mice with severe combined immunodeficiency (SCID), human pluripotent stem cell-derived (PSC-derived) neural progenitors migrate a long distance and differentiate to astrocytes that nearly replace their mouse counterparts over a 9-month period. The human PSC-derived astrocytes formed networks through their processes, encircled endogenous neurons, and extended end feet that wrapped around blood vessels without altering locomotion behaviors, suggesting structural, and potentially functional, integration into the adult mouse spinal cord. Furthermore, in SCID mice transplanted with neural progenitors derived from induced PSCs from patients with ALS, astrocytes were generated and distributed to a similar degree as that seen in mice transplanted with healthy progenitors; however, these mice exhibited motor deficit, highlighting functional integration of the human-derived astrocytes. Together, these results indicate that this chimeric animal model has potential for further investigating the roles of human astrocytes in disease pathogenesis and repair.
星形胶质细胞是稳态神经网络的重要组成部分，也是几乎所有神经系统疾病发病机制和恢复过程中的积极参与者。从进化角度来看，与低等脊椎动物和非人类灵长类动物相比，人类的星形胶质细胞与神经元的比例有所增加；然而，缺乏有效的模型阻碍了对完整成年动物中人类星形胶质细胞复杂作用的研究。在此，我们证明，将人类多能干细胞衍生的（PSC衍生的）神经祖细胞移植到严重联合免疫缺陷（SCID）成年小鼠的颈脊髓后，它们会远距离迁移并分化为星形胶质细胞，在9个月的时间里几乎取代了小鼠自身的星形胶质细胞。人类PSC衍生的星形胶质细胞通过其突起形成网络，环绕内源性神经元，并伸出终足包裹血管，且不改变运动行为，这表明它们在结构上以及可能在功能上整合到了成年小鼠脊髓中。此外，在移植了来自肌萎缩侧索硬化症（ALS）患者诱导PSC衍生的神经祖细胞的SCID小鼠中，星形胶质细胞的生成和分布程度与移植健康祖细胞的小鼠相似；然而，这些小鼠表现出运动缺陷，突出了人类来源星形胶质细胞的功能整合。总之，这些结果表明，这种嵌合动物模型有潜力进一步研究人类星形胶质细胞在疾病发病机制和修复中的作用。
