BACKGROUND Autism is a heterogeneous collection of disorders with a complex molecular underpinning. Evidence from postmortem brain studies have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from individuals with autism with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism. METHODS iPSCs were generated from 9 unrelated individuals with autism without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing control individuals. iPSCs were differentiated toward either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterize iPSCs at different stages of differentiation. RESULTS A subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to postmortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated toward a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs. CONCLUSIONS Taken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.

中文翻译：

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自闭症患者诱导多能干细胞（iPSC）的非典型神经发生


背景自闭症是具有复杂分子基础的异质性疾病的集合。死后大脑研究的证据表明，自闭症患者的早期产前发育可能会发生改变。从患有大头畸形的自闭症个体中产生的诱导多能干细胞（iPSC）也表明产前发育是这种情况的关键时期。但对于自闭症产前阶段早期改变的细胞事件知之甚少。方法 iPSC 是由 9 名无亲属关系、无大头畸形且具有异质遗传背景的自闭症个体和 6 名典型发育对照个体产生的。 iPSC 分化为皮质或中脑命运。基因表达和高通量细胞表型分析用于表征不同分化阶段的 iPSC。结果 对自闭症 iPSC 皮质神经元的一个子集进行了 RNA 测序，以揭示与死后大脑研究类似的自闭症特异性特征，表明潜在的共同生物学机制。向皮质命运分化的自闭症 iPSC 在自我形成神经玫瑰花结的能力方面表现出损伤。此外，自闭症 iPSC 在皮质前体细胞和背侧和腹侧前脑前体细胞类型分配率方面表现出显着差异。与之前的研究不同，这些细胞表型是在皮质分化过程中细胞增殖没有改变的情况下发生的。对照 iPSC 和自闭症 iPSC 之间，中脑分化过程中细胞命运的获得没有差异。结论 综上所述，我们的数据表明，在神经发育的早期阶段，自闭症 iPSC 在细胞水平上与对照 iPSC 不同。 这表明与自闭症相关的独特发育差异可能在产前早期就已确定。