Modeling And Dynamical Analysis Of Cell Fate Decision

Cell is the basic unit of organisms, controlling life activities and molecular interactions. Cell fate decision happens during the whole life, and it is also the basis for cell growth, development, disease and apoptosis. Under the normal circumstances, cell fate decision is dependent on the balance between biological molecular network and environment. New and emerging high throughput technologies are allowing us to construct the network of cell fate determination with ever increasing detail. However, it is becoming clear that cell fate specification is a fundamentally complex process, which makes it difficult to predict cell behavior from regulatory network. The applications of systems biology have been successfully handled the data accumulation challenge. Recently, dynamical modeling of molecular networks is one of the most important theories in systems biology, and it is considered to be the most appropriate approach to explore complex biological systems. Based on the theory of dynamic modeling, we address the important issues of cell fate determination, and further develop some mathematical model. Here, we describe the main works in this thesis as follows:(1)Bifurcation dynamics and determination of alternate cell fates in stem cells.The gene regulatory networks in which two lineage-affiliated transcription factors, such as GATA1 and PU.1, inhibit each other but activate themselves so as to regulate the choice between alternative cell fates have been extensively studied. These simple networks can generate bistability and explain the transitions between the alternative cell fates. The commitment of a progenitor cell to a new fate corresponds to the occurrence of different types of bifurcations, depending on the symmetry of the system and the perturbations affect on the system. In this chapter, a general modeling and analyzing approach was used and the results showed that both symmetry and asymmetry systems can lead to different bifurcation dynamics. Especially, if cell fate decision-making is initiated with asymmetry or symmetry-breaking perturbations, a progenitor cell pre-patterns itself into a polarized cell, depending on the asymmetry or symmetry-breaking perturbations. This study may help us understand the fundamental features of binary cell fate decisions more clearly and further apply to a wider range of decision-making processes.(2)Neural fate decision mediated by combinatorial regulation of Hesl and miR-9.In the nervous system, Hesl shows an oscillatory manner in neural progenitors, but a persistent one in neurons. Many models involving Hesl have been provided for the studies of neural differentiation, but few of them take the role of microRNA into account. It is known that a microRNA, miR-9, plays crucial roles in modulating Hesl oscillations. However, the mechanisms underlie are less clear, and still need further investigation. Here we provide a mathematical model to show the interaction between miR-9 and Hesl, with the aim of understanding how the Hesl oscillations are produced, how they are controlled, and further how they are terminated. Based on the experimental findings, the model demonstrates the essential roles of Hesl and miR-9 in regulating the dynamics of the system. In particular, the model suggests that the balance between miR-9 and Hesl plays important roles for the choice between progenitor maintenance and neural differentiation. In addition, synergistic (or antagonistic) effects of several important regulations are investigated so as to elucidate the effects of combinatorial regulation in neural decision-making. Our model provides a qualitative mechanism for understanding the process in neural fate decisions regulated by Hesl and miR-9.(3)Neural fate decision mediated by oscillatory and sustained Hesl.During development of central nervous system, Hesl proteins show short pe-riod oscillations in progenitor cells, while stable low levels in neurons. The reason why diverse expression modes of Hesl exist remains unknown. Here, we develop a mathematical model involving Hesl and BM88, with the aim of understanding the complex molecular mechanism that orchestrates the processes of neural fate decisions. The simple but fundamental model can account for both Hesl oscillations observed in neural progenitors and regulation of BM88 by Hesl in the differentiation progress. These results suggest that a relatively simple network is capable of accounting for some fundamental principles in progenitor maintenance and neural differentiation.