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

被引:6
作者
Teague, Seth [1 ]
Primavera, Gillian [1 ]
Chen, Bohan [2 ]
Liu, Zong-Yuan [3 ]
Yao, LiAng [3 ]
Freeburne, Emily [3 ]
Khan, Hina [3 ]
Jo, Kyoung [3 ]
Johnson, Craig [3 ]
Heemskerk, Idse [1 ,2 ,3 ,4 ,5 ]
机构
[1] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Computat Med & Bioinformat, Med Sch, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Dept Cell & Dev Biol, Med Sch, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Ctr Cell Plast & Organ Design, Med Sch, Ann Arbor, MI 48109 USA
[5] Univ Michigan, Dept Phys, Ann Arbor, MI 48109 USA
关键词
POSITIONAL INFORMATION; PLURIPOTENCY FACTORS; MORPHOGEN; GRADIENT; DYNAMICS; DIFFERENTIATION; TRANSCRIPTION; COMMITMENT; INDUCTION; IDENTITY;
D O I
10.1038/s41467-024-45719-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. The interpretation of the key developmental signal BMP remains poorly understood. Here, the authors show that the total time-integrated signaling controls differentiation in a stem cell embryo model and provide a possible mechanism.
引用
收藏
页数:18
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