The combined activity of four transcription factors (Oct4, Sox2, cMyc and Klf4) can reprogram adult cells into induced pluripotent stem (iPS) cells. These reprogrammed cells should provide a limitless supply of genetically tailored cell types for transplantation medicine, drug discovery and the study of human disease. Unfortunately, the methods used to deliver reprogramming factors have either raised concerns regarding the future utility of the resulting stem cells, or may not be compatible with industrial scale production of clinically compatible stem cell lines. Here, we propose to determine the mechanisms of action of small molecules that we have shown can facilitate the reprogramming process by either increasing its efficiency or by allowing the omission of one or more reprogramming factors. Our final goal is to move towards the identification of a chemical formulation that can alone reprogram adult cells to a pluripotent state. These reprogrammed cells would be free of genetic manipulation and would be the optimal pluripotent cells for biomedical applications. Specifically the aims are:
aim 1) To determine the mechanisms by which newly identified small reprogramming molecules act to replace Klf4 in the reprogramming process;
aim 2) To determine the mechanisms by which newly identified small reprogramming molecules that can replace Oct4 act in the reprogramming process;
aim 3) To determine whether the reprogramming molecules that we have identified can act synergistically to replace multiple reprogramming transcription factors, thus moving us closer to a completely chemical method for reprogramming.

Public Health Relevance

When the reprogramming of human somatic cells to a pluripotent state is combined with directed differentiation of the resulting stem cells, a robust supply of genetically tailored, differentiated cells can be produced. There is considerable interest in using these disease and patient-specific cell-types for disease modeling, drug discovery and transplantation medicine. However, the various methods routinely employed for reprogramming currently limit the utility of the resulting stem cell lines. Here, we propose to determine the mechanism of action of small reprogramming molecules that we have already identified and to combine their activities to attempt complete chemical reprogramming. The resulting chemical reprogramming method would provide an optimal approach for efforts that are aimed towards translational goals.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Haynes, Susan R
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Harvard University
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
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Ichida, Justin K; Staats, Kim A; Davis-Dusenbery, Brandi N et al. (2018) Comparative genomic analysis of embryonic, lineage-converted and stem cell-derived motor neurons. Development 145:
Ichida, Justin K; Tcw, Julia; Williams, Luis A et al. (2014) Notch inhibition allows oncogene-independent generation of iPS cells. Nat Chem Biol 10:632-639