Simulations of Astrocyte Induction by Transient Overexpression

Abstract: Astrocytes are one of the most common types of cells found in the central nervous system, and they play an important supportive role for neurons and other brain cells. In order to obtain astrocytes for medical or experimental purposes, some protocols enable the production of astrocytes from stem cells, but it is of interest to be able to produce astrocytes from fibroblasts, a cell type found in the skin. By forcing cells to produce specific proteins, it is possible to change a cells specialization, and the goal of this thesis is to model the molecular dynamics that occur during astrocyte formation when starting either from stem or fibroblast cells. A multi-level model is proposed, with interactions inspired by literature, including genetic and epigenetic regulations. Model simulations are conducted with overexpression of NFIA and Sox9; and overexpression of NFIA in the presence of LIF, which is predicted to result in that the stem and fibroblast cell states will move into the astrocyte state. Experimental findings validate the model's predictions. The results are also indicative of new experiments and given more experimental data to optimize the parameters, the model will be able to offer recipes for fine-tuning astrocyte production protocols.