Human-derived neural progenitors functionally replace astrocytes in adult mice
Human-derived neural progenitors functionally replace astrocytes in adult mice
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人源性神经祖细胞在功能上取代成年小鼠的星形胶质细胞
DOI：
10.1172/jci69097
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发表时间：
2015-03-01
影响因子：
15.9
通讯作者：
Zhang, Su-Chun
中科院分区：
文献类型：
--
作者：
Chen, Hong;Qian, Kun;Zhang, Su-Chun
星形胶质细胞是稳态神经网络的组成部分，也是几乎所有神经系统疾病的发病机制和恢复的积极参与者。在进化上，与低等脊椎动物和非人灵长类动物相比，人类星形胶质细胞与神经元的比例增加;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。在这里，我们证明了在移植到患有严重联合免疫缺陷（SCID）的成年小鼠的颈脊髓后，人多能干细胞衍生的（PSC衍生的）神经祖细胞迁移了很长的距离，并分化为星形胶质细胞，在9个月的时间内几乎取代了它们的小鼠对应物。人PSC衍生的星形胶质细胞通过其过程形成网络，包围内源性神经元，并延伸末端足，其缠绕在血管周围而不改变运动行为，这表明结构和潜在功能整合到成年小鼠脊髓中。此外，在移植有来自ALS患者的诱导PSC的神经祖细胞的SCID小鼠中，星形胶质细胞的产生和分布与移植有健康祖细胞的小鼠中所见的程度相似;然而，这些小鼠表现出运动缺陷，突出了人源性星形胶质细胞的功能整合。总之，这些结果表明，这种嵌合动物模型具有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的潜力。
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.