Zubaidah Ningsih, Nguyen H. N. Tran, Andrew H. A. Clayton
Advances in microfluidics, optogenetics and electronics have enabled the study of dynamically controlled inputs on cellular fate. Here, we applied a microfluidic system to deliver periodic inputs of growth factors to pheochromocytoma cells and measured the extent of premature differentiation as a function of input frequency. Epidermal growth factor-triggered differentiation peaked at two cycles/hour, while nerve growth factor-triggered differentiation peaked at one cycle/hour. To interpret the results, we analyzed a published model that attributed pheochromocytoma cell differentiation to the linear combination of activated enzymes extracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), protein kinase B (AKT) and c-Jun N-terminal kinase (JNK) at specific times after step input stimulation. Transfer functions for enzyme activation were derived from the published time-domain activation kinetics and these transfer functions were combined in a parallel architecture as a predictor of neurite outgrowth, as a function of input frequency. Qualitative agreement was observed between the model and the experiments. © 2025 by the authors.
Department of Chemistry, Faculty of Mathematics and Natural Sciences, Brawijaya University, Jl. Veteran, Malang, 65145, Indonesia; Department of Physics and Astronomy, Optical Sciences Centre, School of Science, Computing and Emerging Technologies, Swinburne University of Technology, Melbourne, 3122, VIC, Australia; Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, 19094, PA, United States
