Lineage reprogramming is a powerful method to study the processes that govern cell fate and may provide an additional approach for cell-based therapies. Among the methods that have been used to reprogram differentiated cells, small molecule approaches offer several unique advantages over genetic- or protein-based techniques. The most significant of these may be that discovery-based methods can be used to identify small molecule probes that control a given reprogramming event, and that such molecules can subsequently be applied to study the underlying biology.This thesis will describe the design, development and implementation of several small molecule screening strategies that were successfully used to identify compounds that reprogram cell fate. First, a platform will be discussed that was used to discover compounds that revert lineage-restricted oligodendrocyte precursor cells to multipotent neural stem cells. Subsequently, a screen will be described that was used to identify chemical complements for the reprogramming factors Klf4 and Sox2 that induce pluripotency in somatic cells. Throughout, emphasis is placed on the mechanistic insights that have been gained by using such compounds as tools to probe this phenomenon. This body of work clearly demonstrates the value of small molecules as tools to study the diverse biological/signaling processes involved in and required for the reprogramming of cell fate. Ultimately, the identification of these and other molecules may help to bring this technology one step closer to clinical application.
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