Department of Reproductive Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Stem Cell Reports. 2017 Apr 11;8(4):843-855. doi: 10.1016/j.stemcr.2017.03.003. Epub 2017 Mar 30.
Astrocytes from familial amyotrophic lateral sclerosis (ALS) patients or transgenic mice are toxic specifically to motor neurons (MNs). It is not known if astrocytes from sporadic ALS (sALS) patients cause MN degeneration in vivo and whether the effect is specific to MNs. By transplanting spinal neural progenitors, derived from sALS and healthy induced pluripotent stem cells (iPSCs), into the cervical spinal cord of adult SCID mice for 9 months, we found that differentiated human astrocytes were present in large areas of the spinal cord, replaced endogenous astrocytes, and contacted neurons to a similar extent. Mice with sALS but not non-ALS cells showed reduced non-MNs numbers followed by MNs in the host spinal cord. The surviving MNs showed reduced inputs from inhibitory neurons and exhibited disorganized neurofilaments and aggregated ubiquitin. Correspondingly, mice with sALS but not non-ALS cells showed declined movement deficits. Thus, sALS iPSC-derived astrocytes cause ALS-like degeneration in both MNs and non-MNs.
家族性肌萎缩侧索硬化症（ALS）患者或转基因小鼠的星形胶质细胞对运动神经元（MNs）具有特异性毒性。目前尚不清楚散发性 ALS（sALS）患者的星形胶质细胞是否会导致 MN 在体内退化，以及这种作用是否特异性针对 MNs。通过将源自 sALS 和健康诱导多能干细胞（iPSCs）的脊髓神经祖细胞移植到成年 SCID 小鼠的颈脊髓中 9 个月，我们发现分化的人星形胶质细胞存在于脊髓的大片区域中，替代了内源性星形胶质细胞，并与神经元接触到类似的程度。具有 sALS 但不具有非 ALS 细胞的小鼠表现出非 MNs 数量减少，随后是 MNs 在宿主脊髓中减少。存活的 MNs 显示出来自抑制性神经元的输入减少，并表现出神经丝紊乱和聚集的泛素。相应地，具有 sALS 但不具有非 ALS 细胞的小鼠表现出运动缺陷的下降。因此，sALS iPSC 衍生的星形胶质细胞可导致 MN 和非 MN 中出现类似 ALS 的退化。
