Epithelial-to-mesenchymal transition proceeds through directional destabilization of multidimensional attractor

How a cell changes from one stable phenotype to another one is a fundamental problem in developmental and cell biology. Currently biologists tackle this problem mainly through trial-and-error. We established a quantitative experimental-theoretical framework to formulate the problem as transitions between nonequilibrium attractors. With the framework we applied modern reaction rate theories in the field. Specifically a central theoretical concept is the reaction coordinate. With our framework we demonstrated that one can perform transition path analyses on measured multi-dimensional transition paths for a cellular system.

Epithelial-to-mesenchymal transition (EMT) is a phenotypic transition process extensively studied recently but mechanistic details remain elusive. Through time-lapse imaging we recorded single cell trajectories of human A549/Vim-RFP cells undergoing EMT induced by different concentrations of TGF-β in a multi-dimensional cell feature space. The trajectories cluster into two distinct groups, indicating that the transition dynamics proceeds through parallel paths. We then reconstructed the reaction coordinates and corresponding pseudo-potentials from the trajectories. The potentials reveal a plausible mechanism for the emergence of the two paths as the original stable epithelial attractor collides with two saddle points sequentially with increased TGF-β concentration, and relaxes to a new one. Functionally the directional saddle-node bifurcation ensures a CPT proceeds towards a specific cell type, as a mechanistic realization of the canalization idea proposed by Waddington.