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Biochemical and Biophysical Regulation of Cell Reprogramming


Cell reprogramming, the reverse process of differentiation, represents a major advancement in cell biology and has wide applications in regenerative medicine, drug screening and disease modeling. Induced pluripotent stem cell (iPSC) reprogramming and direct conversion are two promising approaches to manipulate cell fate. Although extensive studies have been conducted on the role of chemical methods and biomaterials in iPSC reprogramming, their effect on direct reprogramming, the process of converting a somatic cell into a distantly related cell type while avoiding a pluripotent state, have not been fully explored. In this dissertation, we demonstrate, for the first time, that small molecules that disrupt the cytoskeleton, more specifically inhibitors of cell contractility, can significantly improve the direct reprogramming of adult fibroblasts into neurons by modulating gene and protein expression. Furthermore, our findings suggest that focal adhesions and the nuclear lamina play a critical role in this direct reprogramming process. In addition to soluble chemical factors from the microenvironment, the physical microenvironment can also strongly influence cellular processes. Thus, we investigated how biophysical factors regulated induced neuronal conversion. We explored the effects of topography on this process, utilizing poly(dimethylsiloxane) (PDMS) microgrooves and electrospun nanofibrous membranes as our bioengineered substrates in conjunction with lentiviral delivery of specific neurogenic transcription factors. We unraveled that nanoscale cues, in comparison to microscale cues, were more effective at promoting induced neuronal reprogramming. The derivation of induced neuronal cells using direct reprogramming not only serves to provide a platform for neurological disease modeling but moreover, holds great promise for personalized medicine as the generation of patient-specific cells can be valuable for drug discovery and the development of new therapeutics.

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