| The extracellular matrix contributes to multiple cellular processes as an adhesive framework and a source of environmental signals. Pluripotent cells are attached to the extracellular matrix as they make cell fate decisions within their stem cell niche. In this thesis, I will present results showing that the ubiquitous extracellular matrix protein fibronectin is required for self-renewal decisions by mouse embryonic stem (ES) cells through its effects on cell adhesion. Undifferentiated ES cells make fibronectin, and self-renewal depends on an intermediate number of cell-fibronectin interactions. Inhibition of fibronectin production by ES cells caused loss of cell adhesion, decreased expression of self-renewal markers, and decreased integrin receptor signaling through focal adhesion kinase (FAK). These effects were reversed by providing the cells with exogenous fibronectin. Conversely, differentiation was also induced by increasing the level of fibronectin over the amount made by self-renewing cells, thereby increasing both cell adhesion to the surface and integrin signaling through FAK, again leading to decreased expression of self-renewal markers. Therefore, fibronectin is a necessary component of the self-renewal signaling pathway and acts synergistically with other self-renewal factors to maintain ES cell pluripotency. |
