Combinatorial BMP4 and activin direct the choice between alternate routes to endoderm in a stem cell model of human gastrulation
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Oliver Inge Elias Copin Jake Cornwall Scoones Borzo Gharibi Irene Rodriguez-Hernandez Pablo Soro-Barrio Molly Strom Probir Chakravarty James Briscoe Silvia SantosAbstract
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.
Journal details
Journal
Developmental Cell
Volume
60
Issue number
23
Pages
3304-3320 .e9
Available online
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10.1016/j.devcel.2025.08.009
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Europe PubMed Central
40930099
Pubmed
40930099
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