Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals.
Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals.
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自闭症患者诱导多能干细胞的非典型神经发生。
DOI：
10.1016/j.biopsych.2020.06.014
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发表时间：
2021-03-01
影响因子：
10.6
通讯作者：
Baron-Cohen S
中科院分区：
文献类型：
--
作者：
Adhya D;Swarup V;Nagy R;Dutan L;Shum C;Valencia-Alarcón EP;Jozwik KM;Mendez MA;Horder J;Loth E;Nowosiad P;Lee I;Skuse D;Flinter FA;Murphy D;McAlonan G;Geschwind DH;Price J;Carroll J;Srivastava DP;Baron-Cohen S
自闭症是一种具有复杂分子基础的异质性疾病集合。来自死后大脑研究的证据表明，自闭症的早期产前发育可能会改变。从患有孤独症和大头畸形的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。但是对于自闭症产前阶段的早期细胞改变事件知之甚少。从9名患有自闭症但无大头畸形且具有异质遗传背景的无关个体和6名通常发育的对照个体产生iPSC。iPSC向皮质或中脑命运分化。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。对自闭症-iPSC皮质神经元的子集进行RNA测序，以揭示与死后大脑研究相似的自闭症特异性特征，表明潜在的共同生物学机制。向皮质命运分化的孤独症-iPSC显示出自我形成神经元的能力受损。此外，孤独症-iPSCs在皮质前体和背侧和腹侧前脑前体的细胞类型分配率方面表现出显著差异。这些细胞表型发生在皮质分化过程中细胞增殖的变化的情况下，不同于以往的研究。在中脑分化过程中获得的细胞命运在对照和自闭症iPSC之间没有不同。总之，我们的数据表明，自闭症-iPSCs在神经发育的早期阶段在细胞水平上与对照-iPSCs不同。这表明与自闭症相关的独特发育差异可能在早期产前阶段就已建立。
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. 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. 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. 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.
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影响因子：
64.5
作者：
Mariani J;Coppola G;Zhang P;Abyzov A;Provini L;Tomasini L;Amenduni M;Szekely A;Palejev D;Wilson M;Gerstein M;Grigorenko EL;Chawarska K;Pelphrey KA;Howe JR;Vaccarino FM
通讯作者：
Vaccarino FM
影响因子：
64.8
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
通讯作者：
Studer, Lorenz
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Lazarus, Matthew S.;Krishnan, Keerthi;Huang, Z. Josh
通讯作者：
Huang, Z. Josh
影响因子：
1.2
作者：
Grabiec, Marta;Hribkova, Hana;Sun, Yuh-Man
通讯作者：
Sun, Yuh-Man