RESEARCH

During mammalian development, stem cells become progressively restricted in the tissue types to which they can give rise, eventually differentiating into a single cell type. Classically, this process was considered irreversible. A growing body of evidence now suggests that lineage-restricted somatic cells are capable of being reprogrammed to a more primitive state. This can be done by ectopic expression of defined genetic factors, via somatic cell nuclear transfer, cell fusion, and/or treatment with exogenous factors.

A means to control these complex processes has profound implications for regenerative therapies. For example, the identification of techniques to control the reprogramming of mammalian cells would ultimately provide a means 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). My research aims to identify small drug like molecules that can mediate reversible lineage commitment. 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.

Early work in the Schultz lab demonstrated, proof of principle, that small molecules can reverse lineage commitment. For example, Schultz et al. found a compound – Reversine – that reverts lineage restricted myoblasts back to the multipotent mesenchymal progenitor state, reendowing them with adipogenic and osteogenic differentiation potential. Similarly, we also demonstrated that global histone acetylation, induced by HDAC inhibition, can reverse the lineage restriction of oligodendrocyte precursor cells thereby expanding their differentiation potential to include the neuronal lineage.

More recently, we have developed screening platforms to systematically identify small molecule and protein factors to replace the reprogramming factors (Oct4, Sox2, Klf4, c-Myc) that induce pluripotency in somatic cells. These efforts have already 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 mechanism by which these compounds are able to substitute for their respective factors during the reversion of a somatic cell back to the pluripotent state.