Elucidation of human induced pluripotent stem cell behaviors in colonies based on a kinetic model

Maintaining the homogeneity of a stem cell population is one of the challenges in bioprocessing prior to therapeutic applications of stem cells. Concerning human induced pluripotent stem cell (hiPSC) colonies cultured on feeder cells, cells at the peripheral region of the colony were found to have a higher average movement rate than cells at the central region of the colony. This spatial difference in average movement rate might lead to spatial heterogeneity of cell fate decision in the colony. We have developed a kinetic model to clarify the origin of this phenomenon which was difficult to understand by in vitro studies alone. Using a kinetic model based on a cellular automaton, we described fundamental cell behaviors including cell division, contact inhibition, cell migration, cell-cell connections, and cell-substrate connections. With all parameter values estimated from experimental data, the appropriateness of our kinetic model was indicated by good agreement between simulated and experimental data. Using the kinetic model, the average cell movement rate in a colony became homogenous after cell division stopped, implying that cell division was the main cause of the observed spatial heterogeneity. The result also showed a directly proportional relationship between the frequency of cell pushing and cell movement rate in the colony, confirming the role of cell division. Our kinetic model is expected to be useful for studying behaviors of hiPSCs and proposing good strategies to improve hiPSC bioprocessing.