Two-gene Modeling Proposes The Potential Mechanism Of Differentiation-Enhancing Cell Interaction

The development of multi-cellular organism involves many binary decisions for lineage commitment, which are controlled by the canonical two-gene switch circuit. Waddington landscape is frequently used in studying such circuit. However, previous researches generally ignored the effect of cell-cell interactions, which, especially the lateral inhibition, have long been known as important roles in development.By introducing such effect into the one-stage model and applying stochastic method, we obtained a multi-attractor system for the general two-gene network. Some attractors can be regarded as stem cell, including naive stem cell and lineage priming stem cell for the symmetrical or nearly symmetrical expressions of the two genes involved in the network; others act as terminal cell types due to the markedly asymmetrical expressions of the two genes. Moreover, the results indicate that enhancing such cell interaction shallows the naive stem cell-like attractors on the landscape; deepens the lineage priming-like attractors at the first stage of the enhancing and shallows them at the second stage; deepens the terminal cell types during the whole enhancing process, which allow us to infer that enhancing cell interaction is a possible mechanism of inducing differentiation. Simulation results about evolutions of the mean first passage times for differentiation and retrodifferentiation are also consistent with the conclusion we inferred above. The simulated paths for differentiation and retrodifferentiation demonstrate the irreversibility of the development system. In addition, we detected that the path for transdifferentiation passes the stem cell under weak cell interaction, whereas the path could also move along the axes under strong one, both of which have been discovered in experiments. We further extended the model to multi-cell system and asymmetrical interaction. By increasing the population size in exponential function, we found that cell proliferation only contributes to the first step of differentiation with an optimal population size existing. In accordance with biological observation, when mixing stem cell with differentiated cell through setting different interaction parameters for different cells, the stem cell is induced to differentiate and differentiated cell easily gets extinct.Our work presents novel insights into the mechanisms of cell differentiation and provides important clues to the experimental field by proposing optimal reprogramming strategies.