小柯机器人

科学家利用多能干细胞揭示人类分节时钟的特点
2020-04-02 16:08

日本京都大学Cantas Alev和日本理化学研究所(RIKEN)生物系统动力学研究中心(BDR)Miki Ebisuya团队合作,利用多能干细胞揭示了人类分节时钟的特点。这一研究成果于2020年4月1日在线发表在《自然》上。

研究人员通过体外诱导多能干细胞逐步形成早体中胚层及其衍生物,以模拟人体细胞发育的不同方面。研究人员最初研究专注于模拟人体分节时钟,它引起了脊椎动物轴向骨骼的分节模式。

分节时钟是一个基本的生物学概念,其被认为是节律性和可控性出现的基础。研究人员观察到核心分节时钟基因(包括HES7和DKK1)的振荡表达,确定了人类分段时钟的周期大约为五个小时,并证明体外诱导的人类早熟中胚层中存在动态波状基因表达。

此外,研究人员鉴定并比较了由多能干细胞诱导的人和小鼠早熟中胚层中的振荡基因,该基因揭示了物种特异性、共享分子组分以及与小鼠和人假定分节时钟相关的通路。随后,使用基于CRISPR -Cas9的基因组编辑技术,研究人员对已经报道的与椎骨节段缺失患者突变(例如脊椎肋骨发育不全)有关的基因(HES7、LFNG、DLL3和MESP2)进行了编辑。

最后对患者和患者衍生的多能干细胞分析显示,在振荡、同步或分化特性方面基因特异性改变。这些发现提供了对人类分节时钟以及与人类轴向骨骼生成相关的疾病的见解。

据了解,多能干细胞被越来越多地用于模拟胚胎发育和器官形成的不同方面。尽管在体外诱导主要中胚层谱系和细胞类型方面的研究取得了进展,但仍缺乏能够概括人类中胚层发育和复杂模式特征的实验室模型系统。

附:英文原文

Title: Recapitulating the human segmentation clock with pluripotent stem cells

Author: Mitsuhiro Matsuda, Yoshihiro Yamanaka, Maya Uemura, Mitsujiro Osawa, Megumu K. Saito, Ayako Nagahashi, Megumi Nishio, Long Guo, Shiro Ikegawa, Satoko Sakurai, Shunsuke Kihara, Thomas L. Maurissen, Michiko Nakamura, Tomoko Matsumoto, Hiroyuki Yoshitomi, Makoto Ikeya, Noriaki Kawakami, Takuya Yamamoto, Knut Woltjen, Miki Ebisuya, Junya Toguchida, Cantas Alev

Issue&Volume: 2020-04-01

Abstract: Pluripotent stem cells are increasingly used to model different aspects of embryogenesis and organ formation1. Despite recent advances in in vitro induction of major mesodermal lineages and cell types2,3, experimental model systems that can recapitulate more complex features of human mesoderm development and patterning are largely missing. Here we used induced pluripotent stem cells for the stepwise in vitro induction of presomitic mesoderm and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modelling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We observed oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours, and demonstrated the presence of dynamic travelling-wave-like gene expression in in vitro-induced human presomitic mesoderm. Furthermore, we identified and compared oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells, which revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Using CRISPR–Cas9-based genome editing technology, we then targeted genes for which mutations in patients with segmentation defects of the vertebrae, such as spondylocostal dysostosis, have been reported (HES7, LFNG, DLL3 and MESP2). Subsequent analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization or differentiation properties. Our findings provide insights into the human segmentation clock as well as diseases associated with human axial skeletogenesis.

DOI: 10.1038/s41586-020-2144-9

Source: https://www.nature.com/articles/s41586-020-2144-9

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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