Modeling of differentiation pattern formation in human induced pluripotent stem cells mediated by BMP4 and its inhibitor noggin secreted from cells

Abstract In vertebrate development, bone morphogenetic protein (BMP) 4 and its inhibitor, Noggin, are important factors determining differentiation patterns along the body axis. In a previous study on the effects of BMP4 on cell differentiation using a perfusion culture chamber and human induced pluripotent stem (iPS) cells, we found that cells located upstream of the chamber differentiated, whereas those located downstream remained undifferentiated. Noggin specifically binds to BMP4 and prevents it from binding to BMP receptors. Therefore, cell differentiation pattern may be attributed to the spatial pattern of secreted Noggin to inhibit differentiation. In this study, we simulated concentrations of BMP4, Noggin, and BMP4-Noggin complex as a reaction-diffusion model, under three experimental conditions. We considered four boundary conditions for differentiation and Noggin secretion. The optimal simulation conditions that mimic cell differentiation were determined by comparing the experimental and simulation results. The simulation demonstrated that the two boundary conditions where cells secreted Noggin before differentiation marker expression, matched the experimental results of our previous work and references. Thus, the spatial pattern of cell differentiation can be attributed to the distribution of Noggin secreted before differentiation marker expression and to the reaction-diffusion of BMP4 and Noggin.