Autonomic parasympathetic neurons (parasymNs) control unconscious body responses, including “rest-and-digest.” ParasymN innervation is important for organ development, and parasymN dysfunction is a hallmark of autonomic neuropathy. However, parasymN function and dysfunction in humans are vastly understudied due to the lack of a model system. Human pluripotent stem cell (hPSC)-derived neurons can fill this void as a versatile platform. Here, we developed a differentiation paradigm detailing the derivation of functional human parasymNs from Schwann cell progenitors. We employ these neurons (1) to assess human autonomic nervous system (ANS) development, (2) to model neuropathy in the genetic disorder familial dysautonomia (FD), (3) to show parasymN dysfunction during SARS-CoV-2 infection, (4) to model the autoimmune disease Sjögren’s syndrome (SS), and (5) to show that parasymNs innervate white adipocytes (WATs) during development and promote WAT maturation. Our model system could become instrumental for future disease modeling and drug discovery studies, as well as for human developmental studies.

中文翻译：

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来自人类多能干细胞的副交感神经元模拟人类疾病和发育

自主副交感神经元（parasymNs）控制无意识的身体反应，包括“休息和消化”。副交感神经支配对于器官发育很重要，副交感功能障碍是自主神经病的标志。然而，由于缺乏模型系统，人类的副症状功能和功能障碍还没有得到充分研究。人类多能干细胞 (hPSC) 衍生的神经元可以作为多功能平台填补这一空白。在这里，我们开发了一种分化范式，详细描述了从雪旺细胞祖细胞中衍生出功能性人类副症状。我们利用这些神经元 (1) 评估人类自主神经系统 (ANS) 发育，(2) 模拟遗传性疾病家族自主神经功能障碍 (FD) 中的神经病变，(3) 显示 SARS-CoV-2 感染期间的副症状功能障碍，( 4) 模拟自身免疫性疾病干燥综合征 (SS)，以及 (5) 证明副症状在发育过程中支配白色脂肪细胞 (WAT) 并促进 WAT 成熟。我们的模型系统可能有助于未来的疾病建模和药物发现研究以及人类发育研究。