The time integral of BMP signaling determines fate in a stem cell model for early human development.
The time integral of BMP signaling determines fate in a stem cell model for early human development.
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BMP 信号传导的时间积分决定了人类早期发育干细胞模型的命运。
DOI：
10.1101/2023.04.10.536068
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Heemskerk,Idse
中科院分区：
文献类型：
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作者：
Teague,Seth;Primavera,Gillian;Chen,Bohan;Freeburne,Emily;Khan,Hina;Jo,Kyoung;Johnson,Craig;Heemskerk,Idse
在人类体内和体外发育过程中，如何在动态背景下解释旁分泌信号以产生多种细胞命运决定仍然知之甚少。在这里，我们报告了一种自动跟踪方法，用于跟踪与大量人类多能干细胞（hPSC）中细胞命运相关的信号历史。使用无偏见的统计方法，我们发现测量的 BMP 信号传导历史与单个细胞的命运密切相关。我们发现 hPSC 中 BMP 响应的变化在信号持续时间上比在水平上变化更大。然而，信号活动的水平和持续时间只能通过改变时间积分来控制细胞命运的选择。因此，在这种情况下，信令持续时间和级别是可以互换的。在用于人类胚胎模式的干细胞模型中，我们表明信号传导历史可以预测命运模式，并且当信号传导受到干扰时，积分模型可以正确预测细胞命运域的变化。我们的数据表明，从机制上讲，BMP 信号传导是由 SOX2 整合的。
How paracrine signals are interpreted to yield multiple cell fate decisions in a dynamic context during human development in vivo and in vitro remains poorly understood. Here we report an automated tracking method to follow signaling histories linked to cell fate in large numbers of human pluripotent stem cells (hPSCs). Using an unbiased statistical approach, we discover that measured BMP signaling history correlates strongly with fate in individual cells. We find that BMP response in hPSCs varies more strongly in the duration of signaling than the level. However, both the level and duration of signaling activity control cell fate choices only by changing the time integral. Therefore, signaling duration and level are interchangeable in this context. In a stem cell model for patterning of the human embryo, we show that signaling histories predict the fate pattern and that the integral model correctly predicts changes in cell fate domains when signaling is perturbed. Our data suggest that mechanistically, BMP signaling is integrated by SOX2.