Interspecies chimeras offer great potential for regenerative medicine and the creation of human disease models. Whether human pluripotent stem cell–derived neurons in an interspecies chimera can differentiate into functional neurons and integrate into host neural circuity is not known. Here, we show, using Engrailed 1 (En1) as a development niche, that human naive-like embryonic stem cells (ESCs) can incorporate into embryonic and adult mouse brains. Human-derived neurons including tyrosine hydroxylase (TH)⁺ neurons integrate into the mouse brain at low efficiency. These TH⁺ neurons have electrophysiologic properties consistent with their human origin. In addition, these human-derived neurons in the mouse brain accumulate pathologic phosphorylated α-synuclein in response to α-synuclein preformed fibrils. Optimization of human/mouse chimeras could be used to study human neuronal differentiation and human brain disorders.

种间嵌合体为再生医学和人类疾病模型的创建提供了巨大的潜力。种间嵌合体中的人类多能干细胞衍生的神经元是否可以分化为功能性神经元并整合到宿主神经回路中尚不清楚。在这里，我们证明，使用 Engrailed 1 ( En1 ) 作为发育利基，人类幼稚胚胎干细胞 (ESC) 可以整合到胚胎和成年小鼠的大脑中。^{包括酪氨酸羟化酶（TH） +}神经元在内的人源神经元以低效率整合到小鼠大脑中。这些 TH ⁺神经元具有与其人类起源一致的电生理特性。此外，小鼠大脑中的这些人源神经元响应 α-突触核蛋白预先形成的原纤维而积累病理性磷酸化 α-突触核蛋白。人/小鼠嵌合体的优化可用于研究人类神经元分化和人类大脑疾病。