Fontaine, M.; Vives, M. J. D.; Saez, M.; Maizels, R.; Finnie, E.; Briscoe, J.; Rand, D. A.

Building a mechanistic understanding of cell fate decisions remains a fundamental goal of developmental biology, with implications for stem cell therapies, regenerative medicine and understanding disease mechanisms. Single-cell transcriptomics provides a detailed picture of the cellular states observed during these decisions, but building quantitative and predictive models from these data remains a challenge. Here, we present dynamic landscape analysis (DLA), a framework that applies dynamical systems theory to identify stable cell states, map transition pathways, and generate a predictive cell fate decision landscape from single-cell data. Applying this framework to vertebrate neural tube development, we reveal that progenitor specification by Sonic Hedgehog (Shh) can be captured in a landscape with an unexpected circular topology, where initially divergent lineages converge through multiple routes. This landscape accurately predicted cellular responses and cell fate allocation for unseen dynamic signalling regimes. By modelling the dynamic responses that drive cell fate decisions, the DLA framework provides a quantitative and generative framework for extracting mechanistic insights from high-dimensional single-cell data.