Beyond metaphor: quantitative reconstruction of Waddington landscape and exploration of cellular behavior.

Originally proposed as a conceptual metaphor, the Waddington landscape was used to illustrate the directional nature of embryonic development and the relative stability of distinct developmental states. While the Waddington landscape offers a valuable conceptual framework for understanding cellular dynamics, its quantitative reconstruction remains a significant challenge in systems biology and biophysics. Recent methodological advances in single-cell omics technologies, computational modeling approaches, and nonlinear dynamical systems theory have facilitated progress toward quantitative reconstruction of the Waddington landscape, thereby transforming this heuristic metaphor into a predictive theoretical framework. In this review, we summarize the theoretical foundations of the Waddington landscape, categorize current computational and mathematical approaches for the Waddington landscape reconstruction. Meanwhile, we highlight the potential applications and inherent limitations of these approaches in characterizing cellular behaviors, predicting cell fate decisions, and modulating developmental trajectories.