唐氏综合症（DS，或三体现象21，T21）是智力残疾最常见的遗传原因。大脑皮层发育的复杂进程的变化导致了DS的神经缺陷，尽管其中的分子和细胞机制还没有完全理解。人类脑器官（CO）源于诱导多能干细胞（iPSCs）的三维（3D）培养，为了更好地理解DS神经病理的新途径。本研究旨在使用泌尿细胞从DS（T21-iPSC）和功能性染色体的个体中生成iPSC，并检查它们分化为在单层培养中生长的神经元和星形胶质细胞以及3D CO的能力。我们采用非整合表达载体生成泌尿细胞源iPSC线，并使用易于使用的系统产生大脑前叶身份的CO。我们观察到，T21和对照泌尿细胞源iPSC线均成功分化为单层培养中的神经元和星形胶质细胞，以及可以再现人类皮质发育早期特征的CO，包括神经前体区的组织、兴奋性和抑制性神经元的编程分化，以及上层和深层皮层神经元和星形胶质细胞。我们的发现首次证明了使用泌尿细胞源iPSC线产生CO模拟DS的适用性。 ©2023。作者（们）在施普林格科学与商业媒体有限公司的排他许可下，属斯普林格自然的组成部分。

Down syndrome (DS, or trisomy 21, T21), is the most common genetic cause of intellectual disability. Alterations in the complex process of cerebral cortex development contribute to the neurological deficits in DS, although the underlying molecular and cellular mechanisms are not completely understood. Human cerebral organoids (COs) derived from three-dimensional (3D) cultures of induced pluripotent stem cells (iPSCs) provide a new avenue for gaining a better understanding of DS neuropathology. In this study, we aimed to generate iPSCs from individuals with DS (T21-iPSCs) and euploid controls using urine-derived cells, which can be easily and noninvasively obtained from most individuals, and examine their ability to differentiate into neurons and astrocytes grown in monolayer cultures, as well as into 3D COs. We employed nonintegrating episomal vectors to generate urine-derived iPSC lines, and a simple-to-use system to produce COs with forebrain identity. We observed that both T21 and control urine-derived iPSC lines successfully differentiate into neurons and astrocytes in monolayer, as well as into COs that recapitulate early features of human cortical development, including organization of neural progenitor zones, programmed differentiation of excitatory and inhibitory neurons, and upper-and deep-layer cortical neurons as well as astrocytes. Our findings demonstrate for the first time the suitability of using urine-derived iPSC lines to produce COs for modeling DS.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.