Time-integrated BMP signaling determines fate in a stem cell model for early human development

Seth Teague, Gillian Primavera, Bohan Chen, Zong-Yuan Liu, LiAng Yao, Emily Freeburne, Hina Khan, Kyoung Jo, Craig Johnson and Idse Heemskerk ()
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Seth Teague: University of Michigan
Gillian Primavera: University of Michigan
Bohan Chen: University of Michigan Medical School
Zong-Yuan Liu: University of Michigan Medical School
LiAng Yao: University of Michigan Medical School
Emily Freeburne: University of Michigan Medical School
Hina Khan: University of Michigan Medical School
Kyoung Jo: University of Michigan Medical School
Craig Johnson: University of Michigan Medical School
Idse Heemskerk: University of Michigan

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45719-9

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