A combined growth kinetics, metabolism and gene expression model for 3D ESC bioprocesses

Abstract

Exploiting the immense potential of embryonic stem cells (ESC) lies in controlling their differentiation towards the desired cell type. Cell culture variables are known to affect ESC pluripotency, one of its defining characteristics. Therefore, we develop a mathematical model coupling cell growth, metabolism and gene expression for an ESC expansion bioprocess. Batch cultures were performed to obtain estimates for model parameters; however, they were unable to maintain cell proliferation and pluripotency levels. When perfusion feeding is administered to the expansion bioprocess, we observe different metabolic characteristics; hence we use global sensitivity analysis (GSA) to identify the most significant model parameters for re-estimation during dynamic feeding conditions. Perfusion feeding negates the sub-optimal nutrient/metabolite conditions found in batch cultures, facilitates the expansion of ESCs and maintains maximal pluripotency levels. The mathematical model herein is able to capture the experimental observations closely for batch and perfusion experiments. We highlight the importance of optimal nutrient/metabolite culture conditions during ESC bioprocess and initiate the development of an in silico design tool for their optimization.