Stem cell fate regulation: computational modeling in the hematopoietic system

Sammanfattning: The ability to sense the surrounding environment and respond to external fluctuations is a fundamental property of cells, the basic unit of life. Although cells can be very different in their composition and structure, they all have specialized molecular mechanisms that allow them to adapt to their environment, by coordinating gene expression and protein production. In this thesis, we focus on a specific type of cells, called stem cells. These are very important, since they have the potential to generate the different types of specialized cells that compose the tissues and organs in our body. More specifically, we study hematopoietic stem cells, which are responsible for producing the different populations of cells that compose our blood system and execute such different tasks as fighting infections, repairing tissues or transporting oxygen. It is fundamental for the organism to have the right number of cells, of the right type, at the right time. We use computational methods to model the molecular mechanisms of gene expression by which individual cells decide their fate within the complex hierarchy that underlies hematopoiesis. The papers in this thesis address these mechanisms at different scales of complexity, and as a consequence use different modeling approaches, supported by experimental data whenever available. In paper I, we address the structure and dynamical properties of hematopoiesis at the population level, by using compartmental modeling and rate equations. In papers II and III we use a large amount of experimental data to infer the architecture of an important gene regulatory circuit. We use deterministic rate equations to describe how the dynamics of each element of the circuit and their interplay can lead to fate decisions. Finally, in papers IV and V, we analyze the process of fate decision at the single-cell level, using stochastic modeling methods. We explore whether commitment to a particular fate involves the coordination of many genes, and whether different molecular routes can lead to a decision.