美国索尔克生物研究所Fred H. Gage课题组的研究认为在自闭症的人诱导多能干细胞（hiPSC）模型中增加的神经祖细胞（NPC）增殖会诱导复制压力相关的基因组不稳定。这一研究成果1月30日在线发表在《细胞—干细胞》上。

他们表示来自患有大头畸形的自闭症谱系障碍（ASD）患者的hiPSC来源的NPC显示出DNA复制程序的改变和DNA损伤的增加。与对照NPC相比，高通量全基因组易位测序（HTGTS）表明，ASD来源的NPC在复制应激易感基因中带有提高的DNA双链断裂，其中一些与ASD发病机理有关。他们的结果提供了一种机制，通过破坏参与细胞-细胞粘附和迁移的长神经基因，将NPC的过度增殖与ASD的发病机制联系起来。

据悉，大头畸形和ASD之间的关联表明，过度的神经生长可能导致ASD。 同时，源自具有早期发育性脑扩张ASD个体的hiPSC来源的NPC本质上比对照NPC增殖的多。

附：英文原文

Title: Increased Neural Progenitor Proliferation in a hiPSC Model of Autism Induces Replication Stress-Associated Genome Instability

Author: Meiyan Wang, Pei-Chi Wei, Christina K. Lim, Iryna S. Gallina, Sara Marshall, Maria C. Marchetto, Frederick W. Alt, Fred H. Gage

Issue&Volume: January 30, 2020

Abstract: The association between macrocephaly and autism spectrum disorder (ASD) suggests thatthe mechanisms underlying excessive neural growth could contribute to ASD pathogenesis.Consistently, neural progenitor cells (NPCs) derived from human induced pluripotentstem cells (hiPSCs) of ASD individuals with early developmental brain enlargementare inherently more proliferative than control NPCs. Here, we show that hiPSC-derivedNPCs from ASD individuals with macrocephaly display an altered DNA replication programand increased DNA damage. When compared with the control NPCs, high-throughput genome-widetranslocation sequencing (HTGTS) demonstrates that ASD-derived NPCs harbored elevatedDNA double-strand breaks in replication stress-susceptible genes, some of which areassociated with ASD pathogenesis. Our results provide a mechanism linking hyperproliferationof NPCs with the pathogenesis of ASD by disrupting long neural genes involved in cell-celladhesion and migration.

DOI: 10.1016/j.stem.2019.12.013

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30571-5