Mammalian Development. A hierarchical depiction of mammalian development highlighting the gradual decrease in cellular potential that accompanies differentiation from a totipotent zygote to the post-mitotic cells that make up an adult organism. Figure adapted from Lyssiotis CA, et al. Angew. Chemie. 2011.

During mammalian development, stem cells become progressively restricted in the types of cells to which they can give rise; ultimately they differentiate into a single type of cell (see Figure inset). Classically, this process was considered irreversible. A growing body of evidence now suggests that lineage-restricted somatic cells can be reprogrammed to a more primitive state. In general, this is achieved using one of two methods – pharmacological intervention and/or genetic modification. The latter involves expressing stem cell factors in somatic cells, whereas the former is done by extrinsically influencing somatic cells to behave like stem cells by pharmacological perturbation of signaling pathways and/or the epigenetic architecture.

A means to reverse the barriers imposed by developmental has profound implications for regenerative therapies. For example, techniques to control the reprogramming of mammalian cells would ultimately provide a way to use an individual's own healthy, abundant, and easily accessible cells (e.g. skin cells) to generate those lost to age related or degenerative disease (e.g. heart muscle, pancreatic beta cells). Costas' research as a member of the Schultz lab was aimed at identifying small drug-like molecules that could mediate reversible lineage commitment.

Specifically, using a cell-based small molecule screening approach, they found that global histone acetylation, induced by HDAC inhibition, can reverse the lineage restriction of oligodendrocyte precursors and thereby expand their differentiation potential to include the neuronal lineage. More recently, Costas and colleagues developed screening platforms to systematically identify small molecule to replace the reprogramming factors (Oct4, Sox2, Klf4, c-Myc) that induce pluripotency in somatic cells. These efforts led to the identification of small molecules capable replacing Klf4 and Sox2, and protocols for the production of iPS cells with reduced reprogramming transcription factor cocktails. Current and future efforts aim to identify the targets and mechanisms by which these compounds are able to substitute for their respective factors during the reversion of a somatic cell back to the pluripotent state. Such compounds have and will continue to further our understanding of the mechanistic intricacies behind reprogramming and may ultimately provide a means to convert accessible cell types to therapeutically desirable lineages.