Combinatorial BMP4 and activin direct the choice between alternate routes to endoderm in a stem cell model of human gastrulation.

IF 8.7 1区生物学 Q1 CELL BIOLOGY

Developmental cell Pub Date : 2025-09-09 DOI:10.1016/j.devcel.2025.08.009

Oliver C K Inge, Elias Copin, Jake Cornwall-Scoones, Borzo Gharibi, Irene Rodriguez-Hernandez, Pablo Soro-Barrio, Molly Strom, Probir Chakravarty, James Briscoe, Silvia D M Santos

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Abstract

Lineage specification requires accurate interpretation of multiple signaling cues. However, how combinatorial signaling histories influence fate outcomes remains unclear. We combined single-cell transcriptomics, live-cell imaging, and mathematical modeling to explore how activin and bone morphogenetic protein 4 (BMP4) guide fate specification during human gastrulation. We see that these signals interact both synergistically and antagonistically to drive fate decisions. We find that definitive endoderm arises from lineage convergence: a direct route from pluripotency and an indirect route via a mesoderm progenitor state. Cells pass through temporal windows of signaling competency, and the relative concentration of activin and BMP4 dictates the trajectory choice. The efficiency between routes is underpinned by a dual role of BMP4 in inducing mesoderm genes while promoting pluripotency exit. This work underscores that the combination of signals a cell is exposed to not only directs its final fate but also the developmental route taken, suggesting lineage convergence enhances robustness in fate specification.

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在人原肠胚干细胞模型中，组合BMP4和激活素指导通往内胚层的替代途径的选择。

谱系规范需要对多个信号线索进行准确的解释。然而，组合信号历史如何影响命运结果仍不清楚。我们结合单细胞转录组学、活细胞成像和数学模型来探索激活素和骨形态发生蛋白4 （BMP4）如何指导人类原肠胚形成过程中的命运规范。我们看到，这些信号相互作用，协同和对抗，以驱动命运的决定。我们发现最终的内胚层起源于谱系趋同：多能性的直接途径和中胚层祖细胞状态的间接途径。细胞通过信号能力的时间窗口，激活素和BMP4的相对浓度决定了轨迹的选择。BMP4在诱导中胚层基因和促进多能性退出的双重作用支持了途径之间的效率。这项工作强调，细胞所暴露的信号组合不仅指导其最终命运，而且还指导其所采取的发育路线，这表明谱系收敛增强了命运规范的稳健性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Developmental cell 生物-发育生物学

CiteScore

18.90

自引率

1.70%

发文量

203

审稿时长

3-6 weeks

期刊介绍： Developmental Cell, established in 2001, is a comprehensive journal that explores a wide range of topics in cell and developmental biology. Our publication encompasses work across various disciplines within biology, with a particular emphasis on investigating the intersections between cell biology, developmental biology, and other related fields. Our primary objective is to present research conducted through a cell biological perspective, addressing the essential mechanisms governing cell function, cellular interactions, and responses to the environment. Moreover, we focus on understanding the collective behavior of cells, culminating in the formation of tissues, organs, and whole organisms, while also investigating the consequences of any malfunctions in these intricate processes.