Reprogramming of human somatic cells back to pluripotent embryonic stem cells

The ability to dedifferentiate or reverse lineage-committed cells to pluripotent/multipotent cells might overcome many of the obstacles (e.g. cell sources, immunocompatibility and bioethical concerns) associated with using other ES and adult stem cells in clinical applications. With an efficient dedifferentiation process, it is conceivable that healthy, abundant and easily accessible somatic cells could be reprogrammed to generate different types of functional cells for the repair of damaged tissues and organs. However, the cellular processes involved in dedifferentiation remain poorly understood, and methods for the control and study of dedifferentiation to pluripotency in human somatic cells are lacking.

Reprogramming of murine somatic cells in embryonic and adult fibroblast cultures to pluripotent ESC-like cells has recently been achieved by simultaneous viral transduction of four transcription factors together. With such proof-of-principle demonstration, next critical steps would be to “translate” such reprogramming methods into human somatic cells and identify small molecules that would allow temporal reversible treatment to induce/enhance reprogramming without risks of genetic manipulations.

Here we propose to develop homogenous human somatic cell systems to examine reprogramming to pluripotency, and implement a high throughput screen of large and diverse chemical librariesy to identify small molecules that can induce/enhance programming of human somatic cells back to pluripotent hESC-like cells. We will further examine their effects/activities via various in-depth cellular/biochemical assays, and characterize their mechanism of action by integrated chemical and functional genomic approaches. Collectively, the studies described in this proposal will provide novel chemical tools for producing unlimited amount of (autologous) pluripotent cells from differentiated/lineage-restricted cells for various applications as well as studying the underlying molecular mechanisms of pluripotency and epigenetic regulations, and may ultimately facilitate development of small molecule therapeutics to stimulate tissue/organ regeneration in vivo.