Frequency-Dependent Premature Differentiation of Pheochromocytoma Cells Exhibits Band-Pass Filter Behavior Correlation with Intracellular Enzyme Activation Kinetics

TL;DR

This study shows how pheochromocytoma cells differentiate in response to periodic growth factor inputs, with enzyme activation patterns influencing the outcome.

Contribution

The novel contribution is linking input frequency to enzyme activation kinetics using a model that predicts differentiation outcomes.

Findings

Differentiation peaks at specific input frequencies for EGF and NGF.

A model combining enzyme activation transfer functions qualitatively matches experimental results.

The system exhibits band-pass filter behavior in response to input frequency.

Abstract

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.

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