Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
Nat Commun. 2021 Aug 6;12(1):4744. doi: 10.1038/s41467-021-24776-4.
Human induced pluripotent stem cells (iPSC) hold promise for modeling diseases in individual human genetic backgrounds and thus for developing precision medicine. Here, we generate sensorimotor organoids containing physiologically functional neuromuscular junctions (NMJs) and apply the model to different subgroups of amyotrophic lateral sclerosis (ALS). Using a range of molecular, genomic, and physiological techniques, we identify and characterize motor neurons and skeletal muscle, along with sensory neurons, astrocytes, microglia, and vasculature. Organoid cultures derived from multiple human iPSC lines generated from individuals with ALS and isogenic lines edited to harbor familial ALS mutations show impairment at the level of the NMJ, as detected by both contraction and immunocytochemical measurements. The physiological resolution of the human NMJ synapse, combined with the generation of major cellular cohorts exerting autonomous and non-cell autonomous effects in motor and sensory diseases, may prove valuable to understand the pathophysiological mechanisms of ALS.
人诱导多能干细胞 (iPSC) 在模拟个体人类遗传背景下的疾病方面具有潜力，因此可以开发精准医学。在这里，我们生成了含有生理功能神经肌肉接头 (NMJ) 的感觉运动器官，并将该模型应用于不同亚组的肌萎缩侧索硬化症 (ALS)。我们使用一系列分子、基因组和生理技术，鉴定和表征运动神经元和骨骼肌，以及感觉神经元、星形胶质细胞、小胶质细胞和血管。从具有 ALS 的个体和编辑以携带家族性 ALS 突变的同基因系衍生的多个人类 iPSC 系生成的类器官培养物在 NMJ 水平表现出损伤，这通过收缩和免疫细胞化学测量均可检测到。人类 NMJ 突触的生理分辨率，结合主要细胞群体的产生，对运动和感觉疾病中的自主和非细胞自主效应具有重要意义，可能有助于理解 ALS 的病理生理机制。
