Changing Fate: Cellular Reprogramming.

摘要

Tissue and organ transplantations have historically been limited to allogenic donor grafts. Allografts can restore some degree of functionality to the transplant site, but they are a less-than-optimal substitute for patient-derived materials, as they require patient immunosuppression. The ideal clinical approach is to replace damaged tissue and organs with grafts grown directly from cells harvested from the patient. The induction of pluripotency in fibroblasts was one of the first experiments to show that cell fate could be reprogrammed, to a pluripotent state, by overexpressing four transcription factors—Oct4, Sox2, Klf4, and Nanog. Later research by other groups discovered that cells could also be directly reprogrammed into other cell types, without going through a pluripotent intermediate step. Direct cell reprogramming presents a method to generate a source of patient-specific graft tissues and organs. In this thesis, I aim to provide a molecular mechanistic model for direct cell reprogramming. Evidence suggests a model in which pioneer molecules make a cell competent for reprogramming by gaining a foothold at key promoter sites, thereby making the binding site accessible to epigenetic modification by chromatin remodeling complexes.