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研究揭示物种特异性发育速率的代谢调节
2023-01-07 14:52

美国哈佛医学院Olivier Pourquié等研究人员合作揭示物种特异性发育速率的代谢调节。相关论文于2023年1月4日在线发表在《自然》杂志上。

通过使用多能干细胞,研究人员建立了一个体外系统,再现了小鼠和人类胚胎之间发育速度的两倍差异。这个系统提供了一个发育速度的定量测量,由分节时钟的周期显示,分节时钟是一个与脊椎前体的节律性生产有关的分子振荡器。通过这个系统,研究人员表明质量特定的代谢率与发育速度成比例,因此小鼠细胞中的代谢率比人类细胞高。通过抑制电子运输链来降低这些代谢率会通过损害细胞的NAD+/NADH氧化还原平衡来减缓分节时钟,并进一步降低蛋白质合成的整体速率。相反,通过过度表达乳酸菌NADH氧化酶LbNOX来增加人类细胞中的NAD+/NADH比率会增加了翻译率并加速分节时钟。这些发现代表了操纵发育速率的一个起点,并具有多种转化应用,包括加速人类多能干细胞的分化,用于疾病建模和基于细胞的治疗。
 
据悉,动物在胚胎发育的速度上显示出巨大的物种间差异,尽管发育事件的整体顺序是广泛的。生物化学反应速率的差异,包括蛋白质的产生和降解速率,被认为是造成物种间发育速率的原因。然而,物种间不同的生化反应速率的原因仍然未知。
 
附:英文原文

Title: Metabolic regulation of species-specific developmental rates

Author: Diaz-Cuadros, Margarete, Miettinen, Teemu P., Skinner, Owen S., Sheedy, Dylan, Daz-Garca, Carlos Manlio, Gapon, Svetlana, Hubaud, Alexis, Yellen, Gary, Manalis, Scott R., Oldham, William M., Pourqui, Olivier

Issue&Volume: 2023-01-04

Abstract: Animals display substantial inter-species variation in the rate of embryonic development despite a broad conservation of the overall sequence of developmental events. Differences in biochemical reaction rates, including the rates of protein production and degradation, are thought to be responsible for species-specific rates of development1,2,3. However, the cause of differential biochemical reaction rates between species remains unknown. Here, using pluripotent stem cells, we have established an in vitro system that recapitulates the twofold difference in developmental rate between mouse and human embryos. This system provides a quantitative measure of developmental speed as revealed by the period of the segmentation clock, a molecular oscillator associated with the rhythmic production of vertebral precursors. Using this system, we show that mass-specific metabolic rates scale with the developmental rate and are therefore higher in mouse cells than in human cells. Reducing these metabolic rates by inhibiting the electron transport chain slowed down the segmentation clock by impairing the cellular NAD+/NADH redox balance and, further downstream, lowering the global rate of protein synthesis. Conversely, increasing the NAD+/NADH ratio in human cells by overexpression of the Lactobacillus brevis NADH oxidase LbNOX increased the translation rate and accelerated the segmentation clock. These findings represent a starting point for the manipulation of developmental rate, with multiple translational applications including accelerating the differentiation of human pluripotent stem cells for disease modelling and cell-based therapies.

DOI: 10.1038/s41586-022-05574-4

Source: https://www.nature.com/articles/s41586-022-05574-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
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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