小柯机器人

利用灵长类细胞融合消除神经发育中的基因调控差异
2021-03-18 16:00

美国斯坦福大学医学院Hunter B. Fraser和Sergiu P. Paca研究团队合作取得一项新突破。他们的最新研究通过融合灵长类细胞消除了神经发育中的基因调控差异。该项研究成果在线发表在2021年3月17日的《自然》上。

研究人员研发了一个新的平台,通过融合人类和黑猩猩诱导的多能干细胞来产生一组四倍体杂交干细胞,从而解决了类器官发育和分化的局限性。通过将这些细胞分化为神经器官,研究人员利用该类器官来研究大脑皮层发育中的物种差异。研究发现杂种类器官为探究跨细胞类型和发育阶段的顺式和反式基因表达差异提供了一个受控系统,从而揭示了与星形胶质细胞相关基因的选择特征。

此外,研究人员还发现人类生长抑素受体基因2(SSTR2)的上调,该基因调节神经元钙信号传导并与神经精神疾病有关。研究人员揭示了皮质神经元中SSTR2的功能调节是人所特有的反应,这突出了该平台在阐明人类进化分子机制的潜力。

研究人员表示,在灵长类动物中,人具有独特的进化轨迹,这是产生人类许多特有特征的原因。但是,无法获得人类与黑猩猩的主要组织限制了对人类进化的研究。使用灵长类动物衍生的诱导多能干细胞进行体外比较研究已经开始揭示细胞和分子水平上的物种差异。尽管类器官的跨物种比较因发育时间和分化变异性差异而变得复杂,但大脑类器官已成为研究体外灵长类动物神经发育的潜在平台。

附:英文原文

Title: Primate cell fusion disentangles gene regulatory divergence in neurodevelopment

Author: Rachel M. Agoglia, Danqiong Sun, Fikri Birey, Se-Jin Yoon, Yuki Miura, Karen Sabatini, Sergiu P. Paca, Hunter B. Fraser

Issue&Volume: 2021-03-17

Abstract: Among primates, humans display a unique trajectory of development that is responsible for the many traits specific to our species. However, the inaccessibility of primary human and chimpanzee tissues has limited our ability to study human evolution. Comparative in vitro approaches using primate-derived induced pluripotent stem cells have begun to reveal species differences on the cellular and molecular levels1,2. In particular, brain organoids have emerged as a promising platform to study primate neural development in vitro3,4,5, although cross-species comparisons of organoids are complicated by differences in developmental timing and variability of differentiation6,7. Here we develop a new platform to address these limitations by fusing human and chimpanzee induced pluripotent stem cells to generate a panel of tetraploid hybrid stem cells. We applied this approach to study species divergence in cerebral cortical development by differentiating these cells into neural organoids. We found that hybrid organoids provide a controlled system for disentangling cis- and trans-acting gene-expression divergence across cell types and developmental stages, revealing a signature of selection on astrocyte-related genes. In addition, we identified an upregulation of the human somatostatin receptor 2 gene (SSTR2), which regulates neuronal calcium signalling and is associated with neuropsychiatric disorders8,9. We reveal a human-specific response to modulation of SSTR2 function in cortical neurons, underscoring the potential of this platform for elucidating the molecular basis of human evolution.

DOI: 10.1038/s41586-021-03343-3

Source: https://www.nature.com/articles/s41586-021-03343-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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