Model-based analysis of spatio-temporal heterogeneity of mouse embryonic stem cells with respect to its functional role in regulating pluripotency

点击翻译按钮获取中文摘要

Mouse embryonic stem (mES) cells are well characterized with respect to their potential for selfrenewal and differentiation in a multitude of different cell types (pluripotency). However, many details about the molecular regulation of pluripotency and the spatial organization of mES cells are still unknown. It is particularly intriguing that different types of heterogeneity seem to play a functional role for the maintenance and regulation of pluripotency. As a prominent example it has been demonstrated for the key transcription factor Nanog that continuously high expression levels are not ultimately required to maintain pluripotency and that the expression levels are in fact variable and reversibly changing. Within the proposed project we will develop a quantitative mathematical models of mES cell organization to address the question if and (if yes) how heterogeneity acts as a functional element for the maintenance of pluripotency. Herein we will combine experimental strategies using different mES cell lines with a multi-level mathematical modelling approach describing mES cell organization from transcription factor networks up to the level of spatially extended cell populations. This approach allows studying the functional role of heterogeneity on the intra- and inter-cellular level, and to derive predictions on how the pluripotent state can be entered, maintained, and exited. The resulting, quantitative models will contribute a comprehensive, systemic understanding of mES cell behaviour, which is ultimately necessary to interfere and to control the fate of (stem) cells in the context of targeted differentiation or reprogramming. The suggested project is divided into two parts. Part I focuses on the intra-cellular dynamics of mES cells and the generation of population inherent heterogeneity with respect to the expression of crucial transcription factors such as Nanog and Rex1. Part II of the project extends the modelling approach to incorporate the dynamics of spatial organization and spatial heterogeneity of mES cells under different culture conditions.