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人类神经元直接重编程证实丙戊酸诱导致畸介质
作者:小柯机器人 发布时间:2019/7/28 18:31:38

斯坦福大学医学院Thomas C. Südhof研究团队近日取得一项新成果。该研究通过直接重编程人类神经元,证明MARCKSL1是丙戊酸致畸性的致病介质。研究成果发表在2019年5月30日出版的《细胞—干细胞》上。

课题组人员发现,尽管直接重新编程的神经元具有快速成熟动力学,但它们可以模拟影响早期神经发育的致畸机制。研究组描述了体外人类神经元重编程过程中成熟的不同阶段,并评估了致畸药物丙戊酸(VPA)的细胞表型。VPA暴露可引起对发育神经元树突状形态和功能特性的慢性损害,但未引起成熟神经元树突状形态和功能特性的损害。这些致病作用与VPA介导的组蛋白去乙酰化酶(HDAC)和糖原合成酶激酶-3 (GSK-3)通路的抑制有关,从而下调许多基因的转录,其中包括MARCKSL1,一种在神经发育早期对树突状形态形成和突触成熟至关重要的光动素稳定蛋白。该研究成果确定了VPA导致发育受限的致病机制,并确立了利用重编程神经元模拟致畸通路这一有效平台。

研究人员表示,人体多能干细胞可通过异位表达proneural转录因子而迅速转化为功能神经元。

附:英文原文

Title: Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity

Author: Soham Chanda, Cheen Euong Ang, Qian Yi Lee, Michael Ghebrial, Daniel Haag, Yohei Shibuya, Marius Wernig, Thomas C. Südhof

Issue&Volume: Volume25,Issue1

Abstract: Human pluripotent stem cells can be rapidly converted into functional neurons by ectopic expression of proneural transcription factors. Here we show that directly reprogrammed neurons, despite their rapid maturation kinetics, can model teratogenic mechanisms that specifically affect early neurodevelopment. We delineated distinct phases of in vitro maturation during reprogramming of human neurons and assessed the cellular phenotypes of valproic acid (VPA), a teratogenic drug. VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons. These pathogenic effects were associated with VPA-mediated inhibition of the histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) pathways, which caused transcriptional downregulation of many genes, including MARCKSL1, an actin-stabilizing protein essential for dendritic morphogenesis and synapse maturation during early neurodevelopment. Our findings identify a developmentally restricted pathogenic mechanism of VPA and establish the use of reprogrammed neurons as an effective platform for modeling teratogenic pathways.

DOI: https://doi.org/10.1016/j.stem.2019.04.021

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30204-8

期刊信息

Cell Stem Cell:《细胞—干细胞》,创刊于2007年。隶属于细胞出版社,最新IF:21.464
官方网址:https://www.cell.com/cell-stem-cell/home
投稿链接:https://www.editorialmanager.com/cell-stem-cell/default.aspx